Transdermal Analgesic Systems with Reduced Abuse Potential

ABSTRACT

A transdermal analgesic system having reduced potential for abuse, wherein the system provides for the controlled release of the antagonist at a rate sufficient to provide an abuse limiting release rate ratio of the antagonist to the analgesic when the dosage form is subject to abuse is disclosed.

RELATED APPLICATION

This application claims the benefit of U.S. Provisional Application No.60/375,110, filed on Apr. 23, 2002.

TECHNICAL FIELD

The present invention relates to a transdermal analgesic system havingreduced potential for abuse. In particular, the invention relates to asystem for transdermal administration of fentanyl and analogs thereof toa subject through intact skin over an extended period of time, whereinthe system provides for the controlled release of the antagonist at arate sufficient to provide an abuse limiting release rate ratio of theantagonist to the analgesic when the dosage form (i.e. the transdermalanalgesic system) is subject to abuse.

BACKGROUND OF THE INVENTION

The transdermal administration of narcotic analgesics, i.e. opioids, forthe treatment of both acute and chronic pain has been described in greatdetail. The following U.S. Pat. Nos. 4,466,953; 4,470,962; 4,588,580;4,626,539; 5,006,342; 5,186,939; 5,310,559; 5,474,783; 5,656,286;5,762,952; 5,948,433; 5,985,317; 5,958,446; 5,993,849; 6,024,976;6,063,399 and 6,139,866 describe various ways of transdermallyadministering fentanyl and analogs thereof, such as alfentanil,carfentanil, lofentanil, remifentanil, sufentanil, trefentanil and thelike, and are incorporated herein by reference. These patents disclosethat fentanyl can be administered from a topically applied ointment,cream, or from a transdermal patch.

The potential for abuse of narcotic analgesics by intranasal, oral orparenteral routes is well known. Diversion and abuse of opioids may takeseveral different forms. For example the medication may be used by aperson for whom it is not intended, i.e., diversion, or in amountsand/or frequency greater than prescribed, either by the originallyprescribed route (e.g., oral or transdermal) or by an alternate route(e.g. parenteral, intravenous, or intranasal). In order to prevent abuseof these substances, it has been proposed to provide dosage forms whichcombine the abusable substance with an amount of an antagonist for theabusable substance sufficient to eliminate the “high” associated withabuse of the substance without eliminating the other therapeuticbenefits for which the drugs are intended to be administered. See, forexample, U.S. Pat. Nos. 3,773,955; 3,493,657; 4,464,378; 4,457,933;4,626,539; 4,806,341; 4,935,428; 5,149,538; and 5,236,714; andInternational Publication No. WO 01/58451A1, all of which areincorporated herein by reference. See also, Talwin; Levine J. D., et al,“Potentiation of pentazocine analgesia by low-dose naloxone”, J ClinInvest 1988; 82:1574-1577; Crain S M, Shen F-K, “Antagonist ofexcitatory opioid receptor function enhance morphine's analgesic potencyand attenuate opioid tolerance/dependence liability”, Pain 2000;84:121-131, which are incorporated herein by reference.

U.S. Pat. No. 5,236,714 describes transdermal dosage forms fordelivering narcotic and psychoactive substances, the dosage form havinga reduced potential for abuse. The transdermal dosage forms comprise ananalgesic reservoir comprising a narcotic and an antagonist, and areleasing means through which the narcotic is released to the body. U.S.Pat. No. 5,149,538 describes a misuse-resistive dosage form fortransdermal administration of opioids. The dosage form comprises anopioid, an antagonist for the opioid that is releasable upon ingestionor solvent immersion, a barrier means separating the opioid from theantagonist and a delivery means for delivering the opioid.

Notwithstanding some success, the existing dosage forms have not beenentirely satisfactory for reducing the potential for abuse, since thenarcotic can be extracted from the dosage form for injection, inhalationor ingestion; or the narcotic and antagonist may interact resulting inadverse physical and/or chemical interaction, such as undesirable ionexchange or permeation of the antagonist into the narcotic reservoirresulting in systemic delivery of the antagonist. Upon prolongedexposure to skin, the antagonist elicits a sensitization response.Further, the existing dosage forms do not provide for the controlledrelease of the antagonist at a rate sufficient to provide an abuselimiting release rate ratio of the antagonist to the narcotic when thedosage form is subject to abuse, e.g., upon ingestion or substantialimmersion of the system in a solvent. When such dosage forms aresubjected to abuse, the antagonist may be isolated at a ratedisproportionate to the release rate of the analgesic from the dosageform, such that the opioid effects of the analgesic are insufficientlyblocked during abuse situations.

SUMMARY OF THE INVENTION

The present invention is directed to the aforementioned needs in theart, and provides a transdermal analgesic system having reducedpotential for abuse, without diminishing the therapeutic or beneficialeffects of the analgesic when the system is applied to the skin, whereinthe system provides for a substantially minimized/negligible skinsensitization response from antagonist exposure. In particular, thetransdermal analgesic system of the present invention provides for thecontrolled release of the antagonist at a rate sufficient to provide anabuse limiting release rate ratio of the antagonist to the analgesicwhen the dosage form is subjected to abuse. Additionally, thetransdermal analgesic system of the present invention provides improvedsafety, e.g., in case of accidental ingestion of a used system bychildren or household pets.

In one aspect, the invention relates to a transdermal system foradministering an analgesic through the skin, the system having a reducedpotential for abuse, comprising:

(a) an analgesic reservoir comprising an analgesic, the analgesic beingselected from the group consisting of fentanyl and analogs thereof;

(b) an antagonist reservoir comprising an antagonist for said analgesic;

(c) a barrier layer, said barrier layer separating said antagonistreservoir from said analgesic reservoir, said barrier layer beingsubstantially impermeable to said analgesic and to said antagonist,wherein the system (i) substantially prevents release of the antagonistfrom the system upon securing the system to a human patient for a periodof up to about 7 days; and (ii) provides release of the antagonist at arate sufficient to provide an abuse limiting release rate ratio of theantagonist to the analgesic when the dosage form is subject to abuse,e.g., upon ingestion or substantial immersion of the system in thesolvent.

In another aspect, the transdermal analgesic system of the inventioncomprises an analgesic reservoir comprising an amount of analgesicsufficient to induce and maintain analgesia in a human patient for aperiod of at least three days, wherein the analgesic is fentanyl or ananalog thereof and the analog is selected from the group consisting ofalfentanil, lofentanil, remifentanil, sufentanil and trefentanil. Inpreferred embodiments, the analgesic is fentanyl or sufentanil, morepreferably, base form of fentanyl or sufentanil.

In additional aspects, the transdermal analgesic system of the inventioncomprises an analgesic reservoir comprising a polymeric matrixcomprising about 1 wt % to about 20 wt % of the analgesic, andoptionally a permeation enhancer. Preferably, the analgesic reservoircomprises a single phase formulation free of undissolved components.

In another aspect, the transdermal analgesic system of the inventioncomprises an analgesic reservoir comprising an aqueous gel comprising upto about 20 wt % of the analgesic, up to about 50 wt % permeationenhancer, and about 0.5 to about 10 wt % gelling agent.

In additional aspects, the transdermal analgesic system of the inventionfurther comprises an analgesic release rate controlling means disposedbetween the analgesic reservoir and the skin. In certain aspects, theanalgesic release rate controlling means is less permeable to theanalgesic than to the permeation enhancer.

In additional aspects, the transdermal analgesic system of the inventioncomprises an antagonist reservoir comprising an antagonist in a formthat is not releasable through the barrier layer, the antagonist beingreleasable from system upon being ingested or substantially immersed ina solvent. Preferably, the antagonist reservoir comprises the antagonistdispersed within a polymer, wherein the antagonist is substantiallyinsoluble in the antagonist reservoir polymer. In certain embodiments,the antagonist is dispersed in a matrix comprising a material thatsubstantially prevents release of the antagonist; or the antagonist iscomplexed with an ionic resin. In additional embodiments, the antagonistreservoir comprises the antagonist in a multiparticulate form, whereineach particle is individually coated with a material that substantiallyprevents release of the antagonist. In additional embodiments, theantagonist reservoir comprises beads coated with the antagonist, whereinthe beads may be formed from glass or an inert or non-dissolvablepolymer, and further wherein the coated beads are optionally coated withor dispersed in material that substantially prevents release of theantagonist. The antagonist is selected from the group consisting ofnaltrexone, methylnaltrexone, naloxone, nalbuphine, nalorphine,nalorphine dinicotinate, nalmefene, nadide, levallorphan, cyclozocineand pharmaceutically acceptable salts thereof. In preferred embodiments,the antagonist is present as a salt, preferably as a hydrochloride saltof an antagonist base.

In additional aspects, the transdermal analgesic system of the inventioncomprises a barrier layer impermeable to the analgesic and theantagonist; wherein the barrier layer comprises a material that isinsoluble in water, alcohol and organic solvents. The antagonistreservoir is disposed on the skin distal surface of the barrier layerand the analgesic reservoir is disposed on the skin proximal surface ofthe barrier layer.

In additional aspects, the transdermal analgesic system of the inventionfurther comprises an antagonist release rate controlling means, whereinsaid antagonist release rate controlling means substantially preventsrelease of the antagonist from the system upon securing the system to ahuman patient for a period of up to about 7 days; and provides releaseof the antagonist at a rate sufficient to provide an abuse limitingrelease rate ratio of the antagonist to the analgesic when the dosageform is subject to abuse, e.g., upon ingestion or substantial immersionof the system in the solvent. The antagonist release rate controllingmeans is disposed on the skin distal surface of the antagonistreservoir.

In another aspect, the transdermal analgesic system of the invention,when the dosage form is subject to abuse, e.g., upon ingestion orimmersion in a solvent for a period of time, substantially continuouslyprovides a release rate ratio of the antagonist to the analgesic ofabout 0.075:1 to about 30:1, about 0.25:1 to about 20:1; about 0.5:1 toabout 16:1; about 0.5:1 to about 14:1; about 0.75:1 to about 12:1; about1:1 to about 10:1, about 1.5:1 to about 8:1; about 2:1 to about 6:1; andabout 2:1 to about 4:1, wherein the period of time of immersion is up toabout 1 minute to about 24 hours.

In another aspect, the invention relates to a transdermal system foradministering an analgesic through the skin, the system having a reducedpotential for abuse, comprising:

(a) an analgesic reservoir comprising an amount of analgesic sufficientto induce and maintain analgesia in a human patient for a period of atleast three days, wherein the analgesic is fentanyl or an analog thereofand the analog is selected from the group consisting of alfentanil,lofentanil, remifentanil, sufentanil and trefentanil;

(b) an antagonist reservoir comprising an antagonist for said analgesic,wherein the antagonist in a form that is not releasable through thebarrier layer, the antagonist being releasable from system upon beingingested or substantially immersed in a solvent, and further wherein theantagonist is selected from the group consisting of naltrexone,methylnaltrexone, naloxone, nalbuphine, nalorphine, nalorphinedinicotinate, nalmefene, nadide, levallorphan, cyclozocine andpharmaceutically acceptable salts thereof;

(c) a barrier layer, said barrier layer separating said antagonistreservoir from said analgesic reservoir, said barrier layer beingsubstantially impermeable to said analgesic and to said antagonist; and

(d) an antagonist release rate controlling means disposed on the skindistal surface of the antagonist reservoir, wherein said antagonistrelease rate controlling means substantially prevents release of theantagonist from the system upon securing the system to a human patientfor a period of up to about 7 days, and further wherein the antagonistrelease rate controlling means provides release of the antagonist at arate sufficient to provide an abuse limiting release rate ratio of theantagonist to the analgesic when the dosage form is subject to abuse,e.g., upon ingestion or substantial immersion of the system in thesolvent.

These and other embodiments of the present invention will readily occurto those of ordinary skill in the art in view of the disclosure herein.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 illustrates a cross-section through a schematic, perspective viewof one embodiment of transdermal analgesic system according to thisinvention.

FIG. 2 illustrates a cross-section view through another embodiment ofthis invention.

FIG. 3 illustrates a cross-section view through another embodiment ofthis invention.

FIG. 4 illustrates a cross-section view through another embodiment ofthis invention.

FIG. 5 illustrates a cross-section view through another embodiment ofthis invention.

FIGS. 6, 7 and 8 illustrate the cumulative release of naltrexone from aPluronic coated-Solupor antagonist release controlling means.

FIGS. 9 and 10 illustrate release rate and cumulative release ofnaltrexone, respectively, from a Celgard 3401 antagonist releasecontrolling means.

FIGS. 11 and 12 illustrate release rate and cumulative release ofnaltrexone, respectively, from an impermeable LDPE antagonist releasecontrolling means.

FIGS. 13 and 14 illustrate release rate and cumulative release ofnaltrexone, respectively, from a Celgard 3501 antagonist releasecontrolling means.

FIGS. 15 and 16 illustrate release rate and cumulative release ofnaltrexone, respectively, from a spun bonded polypropylene antagonistrelease controlling means.

FIGS. 17 and 18 illustrate the effect of naltrexone onsufentanil-induced clinical signs in rats within 30 minutes afterdosing.

FIG. 19 illustrates serum fentanyl concentrations following transdermalapplication of various fentanyl systems for 72 hours, over a period of120 hours post application.

FIG. 20 illustrates serum fentanyl concentrations following transdermalapplication of various fentanyl systems for 72 hours, over a period of120 hours post application.

FIG. 21 illustrates plasma sufentanil concentrations following varioussufentanil treatments, up to 120 hours after first administration.

DETAILED DESCRIPTION OF THE INVENTION Overview

The present invention is directed to a transdermal analgesic systemhaving reduced potential for abuse, without diminishing the therapeuticor beneficial effects of the analgesic when the system is applied to theskin. In particular, the system of the present invention provides forthe controlled release of the antagonist at a rate sufficient to providean abuse limiting release rate ratio of the antagonist to the analgesicwhen the dosage form is subject to abuse, wherein the system providesfor a substantially minimized/negligible skin sensitization responsefrom antagonist exposure.

The practice of the present invention will employ, unless otherwiseindicated, conventional methods used by those in pharmaceutical productdevelopment within those of skill of the art. Such techniques areexplained fully in the literature. See, e.g., Gale, R., Chandrasekaran,S. K., Swanson, D. and Wright, J., “Use of Osmotically ActiveTherapeutic Agents in Monolithic Systems” J. Membrane Sci., 7 (1980),319-331; Patini, G. A. and Chain, Y. W., Swarbrick, J. and Boylan, J.C., eds, Encyclopedia of Pharmaceutical Technology, New York: MarcelDekker, Inc., 1999 and Gale, R., Hunt, J. and Prevo, M., Mathiowitz, E.,ed, Encyclopedia of Controlled Drug Delivery Patches, Passive, New York:J Wiley & Sons, Inc, 1999. All patents, patent applications, andpublications mentioned herein, whether supra or infra, are herebyincorporated by reference in their entirety.

Definitions

In describing and claiming the present invention, the followingterminology will be used in accordance with the definitions set outbelow.

The singular forms “a,” “an” and “the” include plural referents unlessthe context clearly dictates otherwise. Thus, for example, reference to“a polymer” includes a single polymer as well as a mixture of two ormore different polymers, reference to “a permeation enhancer” includes asingle permeation enhancer as well as two or more different permeationenhancer in combination, and the like.

As used herein, the terms “analgesic” and “drug” are usedinterchangeably and refer to fentanyl and an analog of fentanyl. As usedherein, the term “an analog of fentanyl” (hereafter referred to as“analog”) refers to extremely potent and effective analgesics suchalfentanil, carfentanil, lofentanil, remifentanil, sufentanil,trefentanil, and the like.

As used herein, the term “substantially prevents release of theantagonist from the system” implies a transdermal analgesic systemwherein minimal amount of antagonist is released from the system uponcasual contact or incidental exposure to water, such that there isminimal antagonist skin contact, thus substantially minimizing skinsensitization response from antagonist exposure.

As used herein, the term “incidental exposure to water” refers toshort-term exposure to high humidity or brief exposure to liquid water,such as during showering, sweat, and the like.

As used herein, the term “subsaturated system” refers to system whereinthe concentration of the analgesic is below its solubility limit. Theanalgesic reservoir comprises a single phase polymeric composition, freeof undissolved components, wherein the analgesic and all othercomponents are present at concentrations no greater than, and preferablyless than, their saturation concentrations in the reservoir.

As used herein, the term “single phase polymeric composition” refers toa composition in which the analgesic and all other components aresolubilized in a polymer and are present at concentrations no greaterthan, and preferably less than, their saturation concentrations in thereservoir such that there are no undissolved components present in thecomposition over a substantial portion of the administration period;wherein all the components in combination with the polymer form a singlephase.

As used herein, the term “component” refers to an element within theanalgesic reservoir, including, but not limited to, an analgesic asdefined above, additives, permeation enhancers, stabilizers, dyes,diluents, plasticizer, tackifying agent, pigments, carriers, inertfillers, antioxidants, excipients, gelling agents, anti-irritants,vasoconstrictors and the like.

As used herein, an “analgesic release controlling means” refers to ameans to modulate the release rate of the analgesic, such as ratecontrol membranes generally known in the art.

As used herein, the term “antagonist release controlling means” refersto a means to control the antagonist release rate and substantiallyminimizing skin sensitization response from antagonist exposure. Theantagonist release controlling means modulates the ingress of solvent into the antagonist reservoir, thus modulating the release of theantagonist during abuse while permitting the release of the antagonistat a rate sufficient to inhibit abuse. The antagonist releasecontrolling means include physical means such as a layer, a membrane, afilm, a coating, a sheet, a deposit, including but not limited to, arate control layer, a rate control membrane, a porous or a microporousmembrane, an impermeable film wherein the release is controlled throughthe edge of the patch. The antagonist release controlling means alsoinclude chemical means and may be osmotically driven, concentrationdependent, or may depend on the size and characteristics of thematerials forming the antagonist release controlling means. In certainembodiments, the antagonist rate controlling means is incorporatedwithin the antagonist reservoir where the rate of release is governed bythe osmotic bursting mechanism cited in Gale, et al., (Gale, R.,Chandrasekaran, S. K., Swanson, D. and Wright, J., “Use of OsmoticallyActive Therapeutic Agents in Monolithic Systems”, J. Membrane Sci., 7(1980), 319-331). The release rate of the antagonist is controlled byfactors such as the amount of antagonist within the antagonistreservoir, the antagonist particle size, antagonist salt osmoticpressure, and physical characteristics of the polymer matrix of theantagonist reservoir.

The “DURAGESIC® fentanyl patch” is used interchangeably with “DUROGESIC™fentanyl patch” and refers to a fentanyl patch as discussed above (seealso Physicians Desk Reference, 56th Edition, 2002, pages 1786-1789).

As used herein, the term “abuse of a transdermal analgesic system”refers to the use of a transdermal analgesic system other than asindicated by the product labeling, including tampering or misusing thesystem, subjecting the system to diversion, ingestion or substantialimmersion of the system in a solvent for intravenous administration,buccal administration, and the like.

As used herein, the term “C_(max) (ng/ml)” refers to the peak blood,plasma or serum concentration of the analgesic, i.e., fentanyl or theanalog thereof.

As used herein, the term “standardized C_(max) (ng/ml-cm²)” refers tothe C_(max) (ng/ml) per unit area (cm²) of the active analgesic deliveryarea of the system, e.g., the area of the analgesic reservoir.

As used herein, the term “normalized C_(max)(ng/ml-(mg/h))” refers tothe C_(max) (ng/ml) divided by the rate of the analgesic administered(mg/h).

As used herein, the term “steady state analgesic flux” refers to theanalgesic flux (in vitro and in vivo) in the range of 1 to 20 μg/h-cm²over a substantial portion of the administration period.

As used herein, the term “bioavailability”, refers to the rate andextent to which the active ingredient or active moiety is absorbed froma drug product and becomes available at the site of action. The rate andextent are established by the pharmacokinetic-parameters, such as, thearea under the blood, plasma or serum drug concentration-time curve(AUC) and the peak, plasma or serum concentration (C_(max)) of the drug.

Two different products are considered to be “bioequivalent” if theyproduce substantially the same pharmacokinetic effects when studiedunder similar experimental conditions. Bioequivalence may bedemonstrated through several in vivo and in vitro methods. Thesemethods, in descending order of preference, include pharmacokinetic,pharmacodynamic, clinical and in vitro studies. In particular,bioequivalence is demonstrated using pharmacokinetic measures such asthe area under the blood, plasma or serum drug concentration-time curve(AUC) and the peak blood, plasma or serum concentration (C_(max)) of thedrug, using statistical criteria as described in greater detailhereinafter.

Two different products are considered to be “pharmacologicallyequivalent” if they produce substantially the same therapeutic effectswhen studied under similar experimental conditions, as demonstratedthrough several in vivo and in vitro methods as described in greaterdetail hereinafter. Therapeutic effects depend on various factors, suchas, potency of the drug, the solubility and diffusivity of the drug inthe skin, thickness of the skin, concentration of the drug within theskin application site, concentration of the drug in the drug reservoir,and the like, as described in greater detail hereinafter. In general,pharmacological equivalence is demonstrated using measures such as thepeak blood, plasma or serum concentration of the drug normalized for therate of drug administered (i.e. normalized C_(max) as defined above) andthe peak blood, plasma or serum concentration of the drug standardizedper unit area of the active drug delivery area of the system (i.e.standardized C_(max) as defined above).

When comparing two different products whose drug administration rate isproportional to the size of the transdermal analgesic system,bioequivalence or pharmacological equivalence may be established eitherby normalizing the peak blood, plasma or serum concentration of the drug(C_(max)) for the rate of drug administered (normalized C_(max)), or bystandardizing the peak blood, plasma or serum concentration of the drug(C_(max)) per unit area of the active drug delivery area of the system(standardized C_(max)). However, when comparing two different productshaving different drug administration rate per unit area, it is necessaryto normalize the peak blood, plasma or serum concentration of the drug(C_(max)) on the basis of the rate of drug administered to establishbioequivalence or pharmacological equivalence.

MODES OF CARRYING OUT THE INVENTION

The present invention provides an analgesic system for transdermaldelivery of fentanyl and analogs thereof for analgetic purposes, to asubject through intact skin over an extended period of time, the systemhaving reduced potential for abuse and a substantiallyminimized/negligible skin sensitization response from antagonistexposure. In particular, the transdermal analgesic system of the presentinvention provides for the controlled release of the antagonist at arate sufficient to provide an abuse limiting release rate ratio of theantagonist to the analgesic when the dosage form is subject to abuse. Inthis regard, the transdermal analgesic system of the invention providesrelease of the antagonist at a rate sufficient to block the opioideffects of the analgesic during abuse situations.

Referring now to FIGS. 1-4 a preferred embodiment of the transdermalanalgesic system according to this invention comprises a patch 1, anantagonist release controlling means 2, an antagonist reservoir 3wherein the skin distal surface of the antagonist reservoir is disposedon the antagonist release controlling means 2, an impermeable barrierlayer 4 wherein the antagonist reservoir 3 is disposed on the skindistal surface of the barrier layer 4, an analgesic reservoir 5 disposedon the skin proximal surface of the barrier layer 4, wherein at leastthe skin contacting surface 6 of the analgesic reservoir 5 is adhesive,and a peelable protective layer 7. In preferred embodiments, theanalgesic reservoir 5 is formed from a pharmaceutically acceptableadhesive. Referring now to FIG. 2, the transdermal analgesic system ofthe invention further comprises an analgesic rate controlling means 8disposed on the skin contacting surface of the analgesic reservoir 6,wherein at least the skin contacting surface of the analgesic ratecontrolling means 8 is adhesive.

Referring now to FIG. 3, the analgesic reservoir 5 is formed from amaterial that does not have adequate adhesive properties. In thisembodiment of a transdermal analgesic system of the invention comprisesa patch 1, wherein the skin-contacting surface of the analgesicreservoir 6 may be formulated with an adhesive coating 9. The analgesicreservoir 5 is a single phase polymeric composition in which theanalgesic and all other components are present at concentrations nogreater than, and probably less than, their saturation concentrations inthe analgesic reservoir 5. This produces a composition in which noundissolved components are present. Referring now to FIG. 4, thetransdermal analgesic system of the invention further comprises ananalgesic rate controlling means 8 disposed on the skin contactingsurface of the analgesic reservoir 6, wherein at least the skincontacting surface of the analgesic rate controlling means 8 isadhesive.

The antagonist release controlling means 2 substantially preventsrelease of the antagonist from the system upon securing the system to ahuman patient for a period of up to about 7 days; substantiallyminimizing skin sensitization response from antagonist exposure; andprovides release of the antagonist at a rate sufficient to provide anabuse limiting release rate ratio of the antagonist to the analgesicwhen the dosage form is subject to abuse, e.g., upon ingestion orsubstantial immersion of the system in the solvent. The antagonistrelease controlling means 2 modulates the ingress of water/solvent in tothe antagonist reservoir, thus modulating the release of the antagonistduring abuse while permitting the release of an antagonist at a ratesufficient to limit abuse. The antagonist release controlling meansinclude physical means such as a membrane, a film, a coating, a sheet, adeposit, including but not limited to, a rate control membrane, a porousor a microporous membrane, an impermeable film wherein the release iscontrolled through the edge of the patch. The antagonist releasecontrolling means also include chemical means and may be osmoticallydriven, concentration dependent, or may depend on the size andcharacteristics of the materials forming the antagonist releasecontrolling means. In certain embodiments, the antagonist ratecontrolling means is incorporated within the antagonist reservoir wherethe rate of release is governed by the osmotic bursting mechanism citedin Gale, et al. The release rate of the antagonist is controlled byfactors such as the amount of antagonist within the antagonistreservoir, the antagonist particle size, antagonist salt osmoticpressure, and physical characteristics of the polymer matrix of theantagonist reservoir.

In preferred embodiments, the antagonist release controlling means 2 maybe a monolithic or a multilaminate layer comprising a material thatsubstantially prevents release of the antagonist from the antagonistreservoir during incidental exposure to moisture. In particular, theantagonist release controlling means 2 comprises a breathable orocclusive material comprising fabric, porous, microporous, spun-bonded,spun laced, track etched, or impermeable material comprising polyvinylacetate, polyvinylidene chloride, polyethylene, polypropylene,polyurethane, polyester, ethylene vinyl acetate (EVA), polyethyleneterephthalate, polybutylene terephthalate, rayon (synthetic textilefibers produced by forcing a cellulose solution through fine spinneretsand solidifying the resulting filaments), wood-pulp, spun lacedpolyester, coated paper products, aluminum sheet, and the like, and acombination thereof. In preferred embodiments, antagonist releasecontrolling means comprises low density polyethylene (LDPE) materials,medium density polyethylene (MDPE) materials or high densitypolyethylene (HDPE) materials, and the like. In preferred embodiments,the release controlling means is a single LDPE layer. In additionalpreferred embodiments, the antagonist release controlling meanscomprises a microporous layer selected from the group consisting ofSolupor microporous ultra high density polyethylene (UHDPE)materials/film (Solupor™ manufactured by DSM Desotech, Denmark),microporous polypropylene (Celgard™ film manufactured by Celgard, Inc.,Charlotte, N.C.), RoTrac Polyester Capillary Pore Membranes (OYPHENGmbH, Germany), spun laced polyester, polypropylene or polyethylene. Themicroporous layer can be further modified with surfactants such asPluracare polyethylene oxide-polypropylene oxide block copolymers (BASF,Wyandotte, Mich.) or hydrophilic polymers such as polyvinylpyrrolidoneto provide additional control over the antagonist release as discussedin greater detail below.

The antagonist release controlling means has a thickness of about 0.012mm (0.5 mil) to about 0.125 mm (5 mil); preferably 0.025 mm (1 mil) toabout 0.1 mm (4 mil); more preferably 0.0375 mm (1.5 mil) to about0.0875 mm (3.5 mil); and even more preferably 0.05 mm (2 mil) to about0.0625 mm (2.5 mil).

The transdermal analgesic system according to this invention comprisesan antagonist reservoir 3, wherein the skin distal surface of theantagonist reservoir is disposed on the antagonist release controllingmeans 2. The antagonist reservoir may be same size as the other layersof the patch or the antagonist may be inset from the edge of the die cutpatch. The antagonist reservoir 3 may be formed from standard materialsas known in the art. For example, the antagonist reservoir is formedfrom a hydrophobic, a lipophilic and/or a non-polar polymeric material,such as, ethyleneoctene copolymers, ethylene-vinyl acetate copolymer(EVA), low density polyethylene (LDPE), high density polyethylene(HDPE), medium density polyethylene (MDPE), styrenic block copolymerthermoplastic elastomers, and the like. In preferred embodiments, theantagonist reservoir 3 is formed from EVA, ethyleneoctene copolymers, asdescribed in greater detail below.

As discussed above, the antagonist reservoir 3 comprises an antagonistin a substantially non-releasable form, when the transdermal analgesicsystem is used as recommended and/or during incidental exposure to water(e.g., sweat, showering, high humidity etc.), the antagonist beingreleasable from the analgesic system when analgesic system is abused,i.e. upon being ingested or substantially immersed in a solvent.Preferably, the antagonist is present in a form that is substantiallyimpermeable to the skin to which the transdermal analgesic system of theinvention is to be applied. The antagonist reservoir comprises anantagonist dispersed within a polymer, wherein the antagonist issubstantially insoluble in the antagonist reservoir polymer. Inpreferred embodiments, the antagonist is present as a salt, preferablyas a hydrochloride salt of an antagonist base. The low solubility of theantagonist in skin and polymer has several advantages, substantiallyminimizing undesirable interactions between the antagonist and theanalgesic, improved stability/shelf life of the transdermal analgesicsystem, and substantially minimizing skin sensitization response fromantagonist exposure.

In certain embodiments, the antagonist is dispersed in a matrixcomprising a polymeric material which substantially prevents release ofthe antagonist, preferably a thermoformable material; or the antagonistis complexed with an ionic resin. In additional embodiments, theantagonist reservoir comprises the antagonist in a multiparticulateform, wherein each particle is individually coated with a polymericmaterial which substantially prevents release of the antagonist, whereinthe polymeric material is preferably a thermoformable material. Inadditional embodiments, the antagonist reservoir comprises beads coatedwith the antagonist, wherein the beads may be formed from glass or aninert or non-dissolvable polymer, and further wherein the coated beadsare optionally coated with or dispersed in a polymeric material whichsubstantially prevents release of the antagonist, wherein the polymericmaterial is preferably a thermoformable material. The antagonist isselected from a group consisting of naltrexone, methylnaltrexone,naloxone, nalbuphine, nalorphine, nalorphine dinicotinate, nalmefene,nadide, levallorphan, cyclozocine and pharmaceutically acceptable saltsthereof. Preferably, the antagonist is present as a salt.

As discussed above, the antagonist reservoir comprises the antagonistdispersed within a polymer. Preferably, the antagonist is dispersed in amatrix comprising a thermoformable material that substantially preventsrelease of the antagonist. Alternatively, the antagonist is present in amultiparticulate form, wherein each particle is individually coated witha polymeric material that substantially prevents release of theantagonist. Preferably, the polymeric material which substantiallyprevents release of the antagonist is hydrophobic—i.e., substantiallyprevents release of the antagonist during normal use, minimizes theamount of antagonist during incidental/casual exposure to solvents(moisture, e.g., sweat, during a shower), and when the dosage form issubject to abuse, e.g., upon ingestion or immersion in a solvent,releases the antagonist in abuse limiting amounts. Preferably, thepolymeric material has a low melting point to allow processing of theantagonist in solid phase and to prevent degradation of the antagonist.Examples of a polymeric material which substantially prevents release ofthe antagonist include, but are not limited to, polyethylene,polyoctene, polyvinyl acetate, polymethyl acrylate, polymethyl acrylate,polyethyl acrylate, polystyrene polymers and copolymers and mixturesthereof; polystyrene copolymers such as styrenic block copolymers (SIS,SBS, SEBS), ethylene copolymers such as polyethyleneoctene copolymers,ethylene-vinyl acetate copolymer (EVA), ethylenemethyl acrylatecopolymers (EMA), ethylene-acrylic add copolymer, ethylene-ethylacrylatecopolymer, and the like, and combinations thereof.

In additional embodiments, the antagonist is complexed with an ionicresin. Examples of ionic resins include, but are not limited tosulfonated polystyrene resins, and the like. Preferably the resincontains a sulfonic acid functionality which when neutralized with theantagonist base forms the sulfonate salt of the antagonist.

In additional embodiments, the antagonist reservoir comprises beadscoated with the antagonist, wherein the spheres or beads may be formedfrom glass, metals or an inert or non-dissolvable polymer, and furtherwherein the coated beads are optionally coated with or dispersed in apolymeric material which substantially prevents release of theantagonist, as described above. The beads may be in any shape, size orform, but are preferably small sized, preferably less than 10 microns.Examples of an inert or non-dissolvable polymer include, but are notlimited to polymethylmethacrylate, polycarbonate and polystyrene.

The antagonist reservoir 3 comprises an amount of the antagonistsufficient to counter analgesic and euphoric effects of the analgesicwhen the transdermal analgesic system is abused. Preferably, theantagonist reservoir comprises about 0.2 to about 15 mg/cm² of theantagonist; more preferably about 0.6 to about 5 mg/cm² of theantagonist; and even more preferably about 0.75 to about 1.5 mg/cm² ofthe antagonist. Preferably, the antagonist reservoir comprises about 20to about 70 wt % of the antagonist; more preferably about 40 to about 65wt % of the antagonist; even more preferably about 50 to about 60 wt %of the antagonist; and even more preferably about 52 to about 56 wt % ofthe antagonist. In preferred embodiments, the antagonist is in the saltform and the preferred antagonists are naltrexone, methylnaltrexone,naloxone, nalbuphine, nalorphine, nalorphine dinicotinate, nalmefene,nadide, levallorphan and cyclozocine.

Preferably, the antagonist is substantially insoluble in the polymerforming the antagonist reservoir 3. In particular, the material formingthe antagonist reservoir 3 has a solubility for the antagonist of about0 wt % to about 1 wt % of the total polymer composition; more preferablyabout 0 wt % to about 0.8 wt %; and even more preferably about 0 wt % toabout 0.5 wt % of the total polymer composition. The antagonistreservoir 3, has a thickness of about 0.0125 mm (0.5 mil) to about 0.1mm (4 mil); preferably about 0.015 mm (0.6 mil) to about 0.0875 mm (3.5mil); more preferably 0.025 mm (1 mil) to about 0.08 mm (3.3 mil); andeven more preferably about 0.025 mm (1 mil) to about 0.075 (3 mil).

The transdermal analgesic system according to this invention comprisesan impermeable barrier layer 4 wherein the antagonist reservoir 3 isdisposed on the skin distal surface of the barrier layer 4, and ananalgesic reservoir 5 is disposed on the skin proximal surface of thebarrier layer 4. The barrier layer 4 is impermeable to the antagonistand the analgesic; and comprises a material which is insoluble in water,alcohol and organic solvents. The barrier layer 4 comprises a polymersuch as polyolefin laminates (Dow Chemical, Midland, Mich.),acrylonitrile copolymer films (BAREX, BP Chemicals, koln, Germany),polyethylnapthalene (PEN), polyethylene terephthalate (PET), polyimide,polyurethane, polyethylene, metallized films and glass coated filmswhere these films can include ethylene copolymers such as ethylene-vinylacetate copolymer (EVA), and combinations thereof. In preferredembodiments, the barrier layer comprises polyester such as PET laminatedto a polymer such as polyurethane, polyethylene, and ethylenecopolymers. In preferred embodiments, the barrier layer comprisespolyester such as PET laminated to ethylene copolymers such asethylene-vinyl acetate copolymer (EVA). The barrier layer as amultilaminate layer has a thickness of about 0.075 mm (0.3 mil) to about0.125 mm (5 mil); preferably 0.025 mm (1 mil) to about 0.1 mm (4 mil);more preferably 0.0625 mm (1.5 mil) to about 0.0875 mm (3.5 mil); andeven more preferably 0.025 mm (1 mil) to about 0.05 mm (2 mil). Thepolyethylene or EVA laminated layer of the preferred PET-PE laminatesimproves the adhesion of the antagonist reservoir to the backing, andserves to prevent the facile removal of the antagonist reservoir fromthe system by the abuser.

The analgesic reservoir 5 is disposed on the skin proximal surface ofthe barrier layer 4, wherein at least the skin contacting surface 6 ofthe analgesic reservoir 5 is adhesive. The analgesic reservoir 5 may beformed from standard materials as known in the art. For example, theanalgesic reservoir is formed from hydrophobic and/or lipophilicpolymeric material, such as, hydrophobic polyurethane, ethylene-vinylacetate copolymer (EVA) and the like. In preferred embodiments, theanalgesic reservoir 5 is formed from a pharmaceutically acceptablepressure sensitive adhesive, preferably a polyacrylate or a styrenicblock copolymer-based adhesive, as described in greater detail below. Inpreferred embodiments, the pressure sensitive adhesive has zero shearviscosity greater than 1-10⁹ poise at 25° centigrade, as determined bythe principle of time-temperature superpositioning of dynamic viscositycurves at various temperatures. This requirement serves to preventadhesive cold flow, and the corresponding increased likelihood foranalgesic-antagonist exchange at the edge of the system.

The adhesive analgesic reservoir 5 or the adhesive coating 9 is formedfrom standard pressure sensitive adhesives known in the art. Examples ofpressure sensitive adhesives include, but are not limited to,polyacrylates, polysiloxanes, polyisobutylene (PIB), polyisoprene,polybutadiene, styrenic block polymers, and the like. Examples ofstyrenic block copolymer-based adhesives include, but are not limitedto, styrene-isoprene-styrene block copolymer (SIS),styrene-butadiene-styrene copolymer (SBS),styrene-ethylenebutene-styrene copolymers (SEGS), and di-block analogsthereof.

The acrylic polymers are comprised of a copolymer or terpolymercomprising at least two or more exemplary components selected from thegroup comprising acrylic acids, alkyl acrylates, methacrylates,copolymerizable secondary monomers or monomers with functional groups.Examples of monomers include, but are not limited to, acrylic acid,methacrylic acid, methoxyethyl acrylate, ethyl acrylate, butyl acrylate,butyl methacrylate, hexyl acrylate, hexyl methacrylate, 2-ethylbutylacrylate, 2-ethylbutyl methacrylate, isooctyl acrylate, isooctylmethacrylate, 2-ethylhexyl acrylate, 2-ethylhexyl methacrylate, decylacrylate, decyl methacrylate, dodecyl acrylate, dodecyl methacrylate,tridecyl acrylate, tridecyl methacrylate, hydroxyethyl acrylate,hydroxypropyl acrylate, acrylamide, dimethylacrylamide, acrylonitrile,dimethylaminoethyl acrylate, dimethylaminoethyl methacrylate,tert-butylaminoethyl acrylate, tert-butylaminoethyl methacrylate,methoxyethyl acrylate, methoxyethyl methacrylate, and the like.Additional examples of appropriate acrylic adhesives suitable in thepractice of the invention are described in Sates, “Acrylic Adhesives,”Handbook of Pressure-Sensitive Adhesive Technology, 2nd ed., pp. 396-456(D. Sates, ed.), Van Nostrand Reinhold, New York (1989). The acrylicadhesives are commercially available (National Starch and ChemicalCorporation, Bridgewater, N.J.; Solutia, Mass.). Further examples ofpolyacrylate-based adhesives are as follows, identified as productnumbers, manufactured by National Starch (Product Bulletin, 2000):87-4098, 87-2287, 87-4287, 87-5216, 87-2051, 87-2052, 87-2054, 87-2196,87-9259, 87-9261, 87-2979, 87-2510, 87-2353, 87-2100, 87-2852, 87-2074,87-2258, 87-9085, 87-9301 and 87-5298.

The acrylic polymers comprise cross-linked and non-cross-linkedpolymers. The polymers are cross-linked by known methods to provide thedesired polymers. In preferred embodiments, the adhesive is apolyacrylate adhesive having a glass transition temperature (Tg) lessthan −10° C., more preferably having a Tg of about −20° C. to about −35°C. The molecular weight of the polyacrylate adhesive, expressed asweight average (MW), generally ranges from 25,000 to 10,000,000,preferably from 50,000 to about 3,000,000 and more preferably from100,000 to 1,000,000 prior to any cross-linking reactions. Uponcross-linking the MW approaches infinity, as known to those involved inthe art of polymer chemistry.

The transdermal analgesic systems comprise analgesic reservoirscomprising a component, including an analgesic at concentration greaterthan, equal to, or less than saturation concentration. As discussedabove, in preferred embodiments the analgesic reservoir 5, comprises asingle phase polymeric composition, free of undissolved components,containing an amount of the analgesic sufficient to induce and maintainanalgesia in a human for at least three days. The analgesic is selectedfrom a group consisting of fentanyl and analogs thereof, such as,alfentanil, carfentanil, lofentanil, remifentanil, sufentanil,trefentanil, and the like. In preferred embodiments, the analgesicreservoir comprises about 0.05 to about 1.75 mg/cm² of analgesic;preferably about 0.07 to about 1.50 mg/cm² of analgesic; preferablyabout 0.08 to about 1.25 mg/cm² of analgesic; more preferably about 0.09to about 1.0 mg/cm² of analgesic; more preferably about 0.1 to about0.75 mg/cm² of analgesic; and even more preferably about 0.12 to about0.5 mg/cm² of analgesic. The analgesic should be soluble in the polymerforming reservoir 3 in a form that is as discussed below. In preferredembodiments, the analgesic is in the base form and the preferredanalgesics are fentanyl or sufentanil. In particularly preferredembodiments, the analgesic reservoir comprises about 0.05 to about 1.75mg/cm² of fentanyl; preferably about 0.07 to about 1.50 mg/cm² offentanyl; preferably about 0.08 to about 1.25 mg/cm² of fentanyl; morepreferably about 0.09 to about 1.0 mg/cm² of fentanyl; more preferablyabout 0.1 to about 0.75 mg/cm² of fentanyl; and even more preferablyabout 0.12 to about 0.5 mg/cm² of fentanyl; wherein fentanyl is in abase form and is completely dissolved. In additionally preferredembodiments, the analgesic reservoir comprises about 0.05 to about 1.75mg/cm² of sufentanil; preferably about 0.07 to about 1.50 mg/cm² ofsufentanil; preferably about 0.08 to about 1.25 mg/cm² of sufentanil;more preferably about 0.09 to about 1.0 mg/cm² of sufentanil; morepreferably about 0.1 to about 0.75 mg/cm² of sufentanil; and morepreferably about 0.12 to about 0.5 mg/cm² of sufentanil; whereinsufentanil is in a base form and is completely dissolved.

The material forming the analgesic reservoir 5 has a solubility for theanalgesic of about 1 wt % to about 25 wt % of the total polymercomposition; preferably about 2 wt % to about 15 wt %; more preferablyabout 4 wt % to about 12 wt % of the total polymer composition; and evenmore preferably about 6 wt % to about 10 wt % of the total polymercomposition. The reservoir 5, with or without the adhesive coating 9,has a thickness of about 0.0125 mm (0.5 mil) to about 0.1 mm (4 mil);preferably about 0.025 mm (1 mil) to about 0.0875 mm (3.5 mil); morepreferably 0.0375 mm (1.5 mil) to about 0.075 (3 mil); and even morepreferably about 0.04 mm (1.6 mil) to about 0.05 mm (2 mil). Inpreferred embodiments, the analgesic is fentanyl, preferably in the baseform, wherein the material forming the reservoir 5 has a solubility forfentanyl of about 1 wt % to about 25 wt % of the total polymercomposition; preferably about 3 wt % to about 15 wt %; more preferablyabout 5 wt % to about 12 wt %; and even more preferably about 7 wt % toabout 10 wt % of the total polymer composition. The reservoir 5, with orwithout the adhesive coating 9, has a thickness of about 0.0125 mm (0.5mil) to about 0.1 mm (4 mil); preferably about 0.025 mm (1 mil) to about0.075 mm (3 mil); more preferably 0.0375 mm (1.5 mil) to about 0.0625(2.5 mil); and even more preferably about 0.04 mm (1.6 mil) to about0.05 mm (2 mil). In additionally preferred embodiments, the analgesic issufentanil, preferably in the base form, wherein the material formingthe reservoir 5 has a solubility for sufentanil of about 1 wt % to about25 wt % of the total polymer composition; preferably about 3 wt % toabout 15 wt %; more preferably about 5 wt % to about 12 wt %; and evenmore preferably about 7 wt % to about 10 wt % of the total polymercomposition. The reservoir 5, with or without the adhesive coating 9,has a thickness of about 0.0125 mm (0.5 mil) to about 0.1 mm (4 mil);preferably about 0.025 mm (1 mil) to about 0.075 mm (3 mil); morepreferably 0.0375 mm (1.5 mil) to about 0.0625 (2.5 mil); and even morepreferably about 0.04 mm (1.6 mil) to about 0.05 mm (2 mil).

In additional embodiments, the analgesic reservoir 5 may optionallycontain additional components such as, additives, permeation enhancers,stabilizers, dyes, diluents, plasticizer, tackifying agent, pigments,carriers, inert fillers, antioxidants, excipients, gelling agents,anti-irritants, vasoconstrictors and other materials as are generallyknown to the transdermal art, provided that such materials are presentbelow saturation concentration in the reservoir.

Examples of permeation enhancers include, but are not limited to, fattyacid esters of glycerin, such as capric, caprylic, dodecyl, oleic acids;fatty acid esters of isosorbide, sucrose, polyethylene glycol; caproyllactylic acid; laureth-2; laureth-2 acetate; laureth-2 benzoate;laureth-3 carboxylic acid; laureth-4; laureth-5 carboxylic acid;oleth-2; glyceryl pyroglutamate oleate; glyceryl oleate; N-lauroylsarcosine; N-myristoyl sarcosine; N-octyl-2-pyrrolidone;lauraminopropionic acid; polypropylene glycol-4-laureth-2; polypropyleneglycol-4-laureth-5-dimethyl lauramide; lauramide diethanolamine (DEA).Preferred enhancers include, but are not limited to, laurylpyroglutamate (LP), glyceryl monolaurate (GML), glyceryl monocaprylate,glyceryl monocaprate, glyceryl monooleate (GMO), and sorbitanmonolaurate. Additional examples of suitable permeation enhancers aredescribed, for example, in U.S. Pat. Nos. 5,785,991; 5,843,468;5,882,676; and 6,004,578.

In certain embodiments, the analgesic reservoir comprises diluentmaterials capable of reducing quick tack, increasing viscosity, and/ortoughening the matrix structure, such as polymethyl methacrylate orpolybutyl methacrylate (ELVACITE, manufactured by ICI Acrylics, e.g.,ELVACITE 1010, ELVACITE 1020, ELVACITE 20), high molecular weightacrylates, i.e., acrylates having an average molecular weight of atleast 500,000, and the like.

In certain embodiments, particularly with styrenic block copolymeradhesive systems, a plasticizer or tackifying agent is incorporated inthe adhesive composition to improve the adhesive characteristics.Examples of suitable tackifying agents include, but are not limited to,aliphatic hydrocarbons; aromatic hydrocarbons; hydrogenated esters;polyterpenes; hydrogenated wood resins; tackifying resins such asESCOREZ, aliphatic hydrocarbon resins made from cationic polymerizationof petrochemical feedstocks or the thermal polymerization and subsequenthydrogenation of petrochemical feedstocks, rosin ester tackifiers, andthe like; mineral oil and combinations thereof.

The tackifying agent employed should be compatible with the blend ofpolymers. For example, the styrenic block copolymers can be formulatedwith rubber compatible tackifying resins, end-block compatible resinssuch polymethyl styrene, or plasticizers such as mineral oil. Generallythe polymer is about 5-50% of the total adhesive composition, thetackifier is about 30-85% of the total adhesive composition, and themineral oil is about 2-40% of total adhesive composition.

The patch 1 further comprises an analgesic rate controlling means 8disposed on the skin contacting surface of the analgesic reservoir 6,wherein at least the skin contacting surface of the analgesic ratecontrolling means 8 is adhesive. The analgesic rate controlling means 8is made of a polymeric material such as ethylene-vinyl acetate (EVA),polyvinyl chloride (PVC), ethylene-ethyl acrylate copolymer, ethylenebutylacrylate copolymer, polyisobutylene (PVC), polyethylene (PE) suchas low density polyethylene (LDPE), medium density polyethylene (MDPE),high density polyethylene (HDPE), and the like, and a combinationthereof; the polymeric materials may be plasticized. In preferredembodiments, the analgesic rate controlling means is adhered to the skinwith an acrylic, silicone, or PIB adhesive material. The analgesic ratecontrolling means has a thickness of about 0.012 mm (0.5 mil) to about0.125 mm (5 mil); preferably 0.025 mm (0.6 mil) to about 0.1 mm (4 mil);more preferably 0.0625 mm (0.8 mil) to about 0.0875 mm (3.5 mil).

The patch 1 further comprises a peelable protective layer 7. Theprotective layer 7 is made of a polymeric material that may beoptionally metallized. Examples of the polymeric materials include,polypropylene, polystyrene, polyimide, polyethylene, polyethyleneterephthalate, polybutylene terephthalate, paper, and the like, and acombination thereof. In preferred embodiments, the protective layercomprises a siliconized polyester sheet.

Referring now to FIG. 5 a preferred embodiment of the transdermalanalgesic system according to this invention comprises a patch 11, anantagonist release controlling means 12, an antagonist reservoir 13wherein the skin distal surface of the antagonist reservoir is disposedon the antagonist release controlling means 12, an impermeable barrierlayer 14 wherein the antagonist reservoir 13 is disposed on the skindistal surface of the barrier layer 14, a pouch formed from theimpermeable barrier layer 14, an analgesic reservoir 15, an analgesicrate controlling means 18, and an amine resistant contact adhesive layer19, covered by a peelable protective layer 17. The impermeable barrierlayer 14 is configured to provide a central volume which contains ananalgesic reservoir 15 in the form of a gel having dissolved andsuspended analgesic therein. Although preferred embodiments of thisinvention utilize an amine resistant in-line adhesive as shown in FIG.5, other means for maintaining the system on the skin can be employed.Such means include a peripheral ring of adhesive outside the path ofanalgesic from the system to the skin, in which case the adhesive neednot be amine resistant. The use of adhesive overlays or other fasteningmeans such as buckles, belts, and elastic arm bands is alsocontemplated. Elements 11, 12, 13, 14, 15, 16, 17, 18 and 19 may be madefrom materials similar to those used in the corresponding elements ofFIGS. 1-4 whereas the analgesic reservoir 15 includes both aqueous andnon-aqueous systems and is preferably an acrylic, silicone orpolyisobutylene-based material, which may be plasticized and containpermeation enhancers, in which the analgesic is dissolved and dispersed.A general formulation for the barrier 13, the analgesic reservoir 15 andthe analgesic rate controlling means of transdermal analgesic systemillustrated in FIG. 5 is as described in U.S. Pat. No. 4,588,580 whichis incorporated herein by reference.

A wide variety of materials which can be used for fabricating thevarious layers of the transdermal analgesic systems according to thisinvention have been described above. This invention thereforecontemplates the use of materials other than those specificallydisclosed herein, including those which may hereafter become known tothe art to be capable of performing the necessary functions.

Administration of the Drug

The present invention provides a transdermal analgesic system havingreduced potential for abuse, without diminishing the therapeutic orbeneficial effects of the analgesic when the system is applied to theskin. As discussed above, the transdermal analgesic system comprises anantagonist in a substantially non-releasable form when the system isused as recommended and/or during incidental exposure to water, theantagonist being releasable from system when the analgesic system isabused, i.e, upon being ingested or substantially immersed in a solvent.In particular, the system of the present invention provides for thecontrolled release of the antagonist at a rate sufficient to provide anabuse limiting release rate ratio of the antagonist to the analgesicwhen the dosage form is subject to abuse. The transdermal analgesicsystem substantially prevents release of the antagonist from the systemupon securing the system to a human patient for a period of up to about7 days. Additionally the system of the invention provides release of theantagonist at a rate sufficient to provide an abuse limiting releaserate ratio of the antagonist to the analgesic when the dosage form issubject to abuse, e.g., upon ingestion or substantial immersion of thesystem in the solvent, as described in greater detail hereinafter.

On application to the skin, the analgesic in the analgesic reservoir (5,15) of the transdermal system (1, 11) diffuses into the skin where it isabsorbed into the bloodstream to produce a systemic analgetic effect.The onset of analgesia depends on various factors, such as, potency ofthe analgesic, the solubility and diffusivity of the analgesic in theskin, thickness of the skin, concentration of the analgesic within theskin application site, concentration of the analgesic in the analgesicreservoir, and the like (see e.g., U.S. Pat. No. 4,588,580 for adiscussion of relative permeabilities and potencies of fentanyl andanalogs thereof). The concentration of the analgesic within the skinapplication sites are also significant in establishing an upper limit onthe size of the transdermal analgesic system and, conversely, the lowerlimit on the usable administration rate, as described in co-pendinginternational Application No. WO 200274286, which is incorporated in itsentirety herein by reference.

When continuous analgesia is desired the depleted transdermal analgesicsystem would be removed and a fresh system is applied to a new location.For example, the transdermal analgesic system would be sequentiallyremoved and replaced with a fresh system at the end of theadministration period to provide relief from chronic pain. Sinceabsorption of the analgesic from the fresh transdermal analgesic systeminto the new application area usually occurs at substantially the samerate as absorption by the body of the residual analgesic within theprevious application site of the transdermal analgesic system, bloodlevels will remain substantially constant. Additionally, it iscontemplated that doses may be increased over time and that concurrentuse of other analgesics may occur to deal with breakthrough pain.

In preferred embodiments, the invention provides for a transdermalanalgesic system exhibiting a normalized C_(max) ranging from about 3.3to about 82.5 ng/ml-(mg/h), preferably about 6.6 to about 50ng/ml-(mg/h), more preferably about 13 to about 40 ng/ml-(mg/h), andeven more preferably from about 20 to about 35 ng/ml-(mg/h); and astandardized C_(max) ranging from about 0.001 to about 0.2 ng/ml-cm²,preferably about 0.005 to about 0.15 ng/ml-cm², more preferably about0.008 to about 0.1 ng/ml-cm², and even more preferably from about 0.01to about 0.08 ng/ml-cm². The transdermal analgesic system comprises atransdermal analgesic system of about 0.5 to about 150 cm²; preferablyabout 2 to about 100 cm²; more preferably about 4 to about 50 cm², andeven more preferably about 10 to about 20 cm². On administration overskin the transdermal analgesic system exhibits a steady state analgesicflux of about 0.1 to about 20 μg/h-cm²; preferably about 0.75 to about10 μg/h-cm²; preferably about 1 to about 8 μg/h-cm²; more preferablyabout 1.5 to about 5 μg/h-cm²; more preferably about 2 to about 3μg/h-cm², and even more preferably about 1 to about 2.5 μg/h-cm².Steady-state administration rates obtainable according to this inventionrange from about 0.1 to about 500 μg/h; preferably about 1 to about 300μg/h; more preferably about 2 to about 250 μg/h; and even morepreferably about 5 to about 200 μg/h.

In additionally preferred embodiments, the invention provides for atransdermal fentanyl system exhibiting a normalized C_(max) ranging fromabout 3.3 to about 82.5 ng/ml-(mg/h), preferably about 10 to about 62ng/ml-(mg/h), more preferably from about 16 to about 41 ng/ml-(mg/h),and even more preferably from about 20 to about 35 ng/ml-(mg/h); and astandardized C_(max) ranging from about 0.01 to about 0.2 ng/ml-cm²,preferably about 0.02 to about 0.15 ng/ml-cm², more preferably fromabout 0.03 to about 0.1 ng/ml-cm², and even more preferably from about0.04 to about 0.08 ng/ml-cm². The transdermal fentanyl system is about 1to about 150 cm²; preferably about 2 to about 125 cm²; more preferablyabout 4 to about 100 cm²; more preferably about 5 to about 75 cm², andeven more preferably about 5 to about 50 cm². On administration overskin, the transdermal fentanyl system exhibits a steady state analgesicflux of about 1 to about 10 μg/h-cm²; preferably about 1.5 to about 8μg/h-cm²; more preferably about 2 to about 5 μg/h-cm², and even morepreferably about 2 to about 3 μg/h-cm². Steady-state administrationrates obtainable for a transdermal fentanyl system according to thisinvention range from about 1 to about 300 μg/h; preferably about 2 toabout 250 μg/h; and more preferably about 5 to about 200 μg/h.

In additionally preferred embodiments, the invention provides for atransdermal sufentanil system exhibiting a normalized C_(max) rangingfrom about 0.04 to about 10 ng/ml-(mg/h), preferably about 1 to about 8ng/ml-(mg/h), and more preferably from about 2 to about 5.5ng/ml-(mg/h), and even more preferably about 2.5 to about 5ng/ml-(mg/h); and a standardized C_(max) ranging from about 0.001 toabout 0.05 ng/ml-cm², preferably about 0.005 to about 0.04 ng/ml-cm²,more preferably from about 0.0075 to about 0.025 ng/ml-cm², and morepreferably from about 0.01 to about 0.02 ng/ml-cm². The transdermalsufentanil system comprises a transdermal analgesic system of about 0.5to about 40 cm²; preferably about 1 to about 35 cm²; and more preferablyabout 2 to about 30 cm². On administration over skin, the transdermalsufentanil system exhibits a steady state analgesic flux of about 0.1 toabout 10 μg/h-cm²; preferably about 0.5 to about 8 μg/h-cm²; morepreferably about 0.75 to about 6 μg/h-cm²; more preferably about 1 toabout 5 μg/h-cm²; and even more preferably about 1 to about 2.5μg/h-cm². Steady-state administration rates obtainable for a sufentanilsystem according to this invention range from about 0.1 to about 200μg/h; preferably about 0.25 to about 150 μg/h; more preferably about 0.5to about 100 μg/h; more preferably about 0.75 to about 50 μg/h; and evenmore preferably about 1 to about 40 μg/h.

Administration is maintained for at least three days, and up to 7 days,with 3-4 day regimen being considered preferable. In preferredembodiments, at least 3%, but not more than 40%, of the total amount ofthe analgesic in the system is administered during approximately thefirst 24 hours of use; at least 6%, but not more than 50%, of the totalamount of the analgesic is administered during approximately the first48 hours of use; and at least 10%, but not more than 75%, of the totalamount of the analgesic is administered during the administrationperiod. In preferred embodiments, the transdermal analgesic system is afentanyl system wherein at least 5%, but not more than 40%, of the totalamount of the analgesic in the system is administered duringapproximately the first 24 hours of use; at least 15%, but not more than50%, of the total amount of the analgesic is administered duringapproximately the first 48 hours of use; and at least 25%, but not morethan 75%, of the total amount of the analgesic is administered duringthe administration period. In alternative embodiments, the transdermalanalgesic system is a sufentanil system wherein at least 3%, but notmore than 40%, of the total amount of the analgesic in the system isadministered during approximately the first 24 hours of use; at least6%, but not more than 50%, of the total amount of the analgesic isadministered during approximately 48 hours of use; and at least 10%, butnot more than 75%, of the total amount of the analgesic is administeredduring the administration period.

As discussed earlier, the transdermal analgesic system of the inventionprovides release of the antagonist at a rate sufficient to provide anabuse limiting release rate ratio of the antagonist to the analgesicwhen the dosage form is subject to abuse, e.g., upon ingestion orsubstantial immersion of the system in the solvent. In this regard, thetransdermal analgesic system of the invention provides release of theantagonist at a rate sufficient to block the opioid effects of theanalgesic during abuse situations. As discussed earlier, and illustratedin the examples, the antagonist release rate is controlled by varyingthe antagonist concentration within the antagonist reservoir, theantagonist salt particle size, the selection of the appropriateantagonist release controlling means, and the processing conditioninvolved in the formation of the transdermal analgesic system. As usedherein, “a release rate ratio” refers to the ratio of a release rate ofthe antagonist to the analgesic over a given period of time measuredusing suitable standard techniques. In this regard, the presentinvention provides a transdermal analgesic system wherein the ratio ofthe amount of antagonist released (i.e. cumulative release) when thepatch is abused to the amount of analgesic released (i.e. cumulativerelease) when the patch is abused is about 0.075:1 to about 30:1, about0.25:1 to about 20:1; about 0.5:1 to about 16:1; about 0.5:1 to about14:1; about 0.75:1 to about 12:1; about 1:1 to about 10:1, about 1.5:1to about 8:1; about 2:1 to about 6:1; and about 2:1 to about 4:1,wherein the period of time of abuse, e.g., ingestion or substantialimmersion of the system in a solvent, is up to about 1 minute to about24 hours, the release based on a standardized test method (e.g. in vitroand in vivo extraction methods) as described in greater detail below. Ifany one of the test methods satisfies the abuse limiting release rateratio of the antagonist to the analgesic, it is deemed to satisfy therequirement that the release rate ratios be abuse limiting.

Examples of in vitro extraction methods are described in greater detailsin the Examples below. In general, the transdermal analgesic system isplaced in a standard extraction medium/solution, equilibrated to thetarget temperature and stirred. Examples of standard extraction mediainclude but are not limited to aqueous medium such as distilled water, asalt solution, aqueous medium containing appropriate buffering agents toprovide a pH of about 1 to 14 (e.g., aqueous medium containing phosphatebuffer at pH 6.5), an aqueous solvent similar to saliva; organicsolvents such as alcohol (e.g. methanol, ethanol, isopropyl alcohol andthe like), dimethylfuran, methylene chloride, chloroform, carbontetrachloride, ether, acetone, benzene, toluene, hexane, pentane,dimethylformamide, formaldehyde, ethyl acetate, methyl ethyl ketone; andcommon household materials such as, nail polish remover, rubbingalcohol, glycerin, mineral spirits, turpentine, vodka, cooking oil,vinegar, gasoline, kerosene, dry cleaning fluids and the like andmixtures thereof. The volume of the medium is adjusted to be below thesolubility limit of the analgesic and the antagonist. The temperature ofthe extraction can be varied within a range of ambient to near that ofboiling, e.g., 25° C., 50° C. and 75° C. Aliquots of the extractionmedium are removed at various time points, e.g., 0, 2, 5, 15, 60 and 120minutes, and diluted with corresponding unused extraction medium. Thesamples are assayed for antagonist and analgesic content by HPLC. If anyone of the test methods satisfies the abuse limiting release rate ratioof the antagonist to the analgesic in any of the above-mentionedextraction medium/solution, it is deemed to satisfy the requirement thatthe release rate ratios be abuse limiting.

Examples of in vivo extraction methods are described in greater detailsin the Examples below. In general the transdermal analgesic systems areplaced in the oral cavity of animals, e.g., mice, rats, pigs, cats,dogs, primates (monkeys), humans, and the like for a predeterminedperiod, e.g., from about 1 minute to about 2 hours. At the end of thetest time period, the transdermal analgesic systems are removed from theoral cavity and allowed to air dry. The transdermal analgesic systemsare analyzed for residual analgesic and antagonist contents usingstandard extraction procedures followed by reverse-phase HPLC analysis.

In certain aspects, the release rate of antagonist into phosphatebuffered medium is controlled by membrane selection or surfactantmodification of the antagonist release controlling means. In general,the lowest release of the antagonist is provided by the polyethylenefilm and the faster release of the antagonist is provided by the Celgardmembrane. The transdermal analgesic systems wherein analgesic isfentanyl, the antagonist is naltrexone, and the antagonist releasecontrolling means comprises Pluronic modified Solupor materials, therelease rate ratio of naltrexone to fentanyl is at least 2:1. Thetransdermal analgesic systems wherein the analgesic is sufentanil, thegreater potency of sufentanil requires a faster antagonist release rate.These faster rates can be provided by an appropriate selection of theantagonist release controlling means such as use of Celgard 3501,various non-woven materials, and exposed antagonist reservoirs where therate of release is controlled by the amount of antagonist within theantagonist reservoir and the antagonist particle size.

In additional aspects, the present invention provides a transdermalanalgesic system wherein the ratio of the amount of antagonistadministered during use to the amount of analgesic administered duringuse is greater than 1:1000, and preferably 1:10,000, depending on theanalgesic and the antagonist used, the concentration of the antagonistin the antagonist reservoir and the selection of the antagonist releasecontrolling means. In additional aspects, the present invention providesa transdermal analgesic system wherein the amount of antagonistadministered during use is 0.1% or less 168 h after administration.Preferably, the amount of antagonist released when the transdermalanalgesic system is abused is 70% or greater after 1, 2, 4, 8 or 24 h ofabuse activities.

A preferred embodiment of this invention is a transdermal analgesicsystem that is bioequivalent to the DURAGESIC® fentanyl system. Inparticular, a monolithic fentanyl system according to the inventionproduces substantially the same pharmacokinetic effects (as measured bythe area under the blood, plasma or serum drug concentration-time curve(AUC) and the peak plasma or serum concentration (C_(max)) of the drug)as compared to the DURAGESIC® transdermal fentanyl system, when studiedunder similar experimental conditions, as described in greater detailhereinafter.

In additional preferred embodiments, a transdermal analgesic system ofthis invention is pharmacologically equivalent to the DURAGESIC®fentanyl system. In particular, a monolithic sufentanil system accordingto the invention produces substantially the same therapeutic effects ascompared to the DURAGESIC® transdermal fentanyl system, when studiedunder similar experimental conditions, as described in greater detailhereinafter.

In general, the standard bioequivalence study is conducted in acrossover fashion in a small number of volunteers, usually with 24 to 36healthy normal adults. Single doses of the drug containing test product,e.g., transdermal fentanyl system according to the invention, andreference product, e.g., DURAGESIC®/DUROGESIC™ fentanyl system, areadministered and blood, plasma or serum levels of the drug are measuredover time. Characteristics of these concentration-time curves, such asthe area under the blood, plasma or serum drug concentration-time curve(AUC) and the peak blood, plasma or serum concentration (C_(max)) of thedrug, are examined by statistical procedures as described in greaterdetail hereinafter. In general, two one-sided statistical tests arecarried out using the log-transformed parameter (AUC and C_(max)) fromthe bioequivalence study. The two one-sided tests are carried out at0.05 level of significance and the 90% confidence interval is computed.The test and the reference formulation/composition are consideredbioequivalent if the confidence interval around the ratio of the mean(test/reference product) value for a pharmacokinetic parameter is noless than 80% on the lower end and no more than 125% on the upper end.

Two different products are generally considered to be “pharmacologicallyequivalent” if they produce substantially the same therapeutic effectswhen studied under similar experimental conditions, as demonstratedthrough several in vivo and in vitro methods as described above.Therapeutic effects depend on various factors, such as, potency of thedrug, the solubility and diffusivity of the drug in the skin, thicknessof the skin, concentration of the drug within the skin application site,concentration of the drug in the drug reservoir, and the like, asdescribed in greater detail hereinafter. In general, pharmacologicalequivalence is demonstrated using measures such as the peak blood,plasma or serum concentration of the drug normalized for the rate ofdrug administered (i.e. normalized C_(max) as defined above) and thepeak blood, plasma or serum concentration of the drug standardized perunit area of the active drug delivery area of the system (i.e.standardized C_(max) as defined above).

When comparing two different products whose drug administration rate isproportional to the size of the transdermal analgesic system, the is nodifference if the peak blood, plasma or serum concentration of the drug(C_(max)) is normalized for the rate of drug administered, orstandardized per unit area of the active drug delivery area of thesystem, in order to establish bioequivalence or pharmacologicalequivalence. However, when comparing two different products havingdifferent drug administration rate per unit area, it is necessary tonormalize the peak blood, plasma or serum concentration of the drug(C_(max)) on the basis of the rate of drug administered to establishbioequivalence or pharmacological equivalence.

Methods of Manufacture

The transdermal analgesic systems are manufactured as follows. Theantagonist reservoir and the analgesic reservoirs are manufacturedaccording to known methodology, as described in greater detail below.

Antagonist Reservoir

The antagonist reservoir can be formed by dry blending an antagonist,preferably an antagonist salt, with a polymeric material, preferable athermoformable material, at high shear and temperature using equipmentsuch as sigma blade mixers or extruders, either batch-wise orcontinuously. The extrudate is calendared to the desired thicknessbetween release liners, followed by lamination at elevated temperatureto a barrier film and/or an analgesic rate controlling means.

In the case of a semi-continuous process, a polymeric material (e.g.,ethylene-vinyl acetate copolymer (28 wt % VA)) is added to one feederhopper of a continuous co-kneader or twin screw extruder (Coperion BussKneader, Stuttgart, Germany) at a rate of about 50 pounds per hour. Anantagonist, preferably an antagonist salt (e.g., naltrexonehydrochloride dihydrate) is added to a second hopper at a rate of 58.7pounds per hour. The extruder is operated to produce extrudate at aconstant rate of approximately one pound per minute. After exiting fromthe extruder, the polymer-drug blend is calendared to a desiredthickness (about 0.03 mm (1.2 mil)) between barrier layer (e.g.,polyester/EVA) and release liner (siliconized polyester film). Thetrilaminate structure is wound on take-up rolls for further processing.

Parameters such as antagonist loading, antagonist reservoir thickness,membrane selection for the analgesic rate controlling means, andsurfactant modification of the analgesic rate controlling means can bevaried to achieve the targeted release rate of antagonist to analgesicfor a variety of abuse circumstances, as illustrated in the Exampleshereinafter. In preferred embodiments, surfactants are coated ontomembrane materials forming the analgesic rate controlling means usingtechniques such as dip-coating, gravure coating, and the like.

Analgesic Reservoir

The transdermal analgesic systems are manufactured according to knownmethodology. A solution of the polymeric analgesic reservoir material,as described above, is added to a double planetary mixer, followed byaddition of desired amounts of the analgesic, preferably fentanyl, morepreferably fentanyl base, and optionally, a permeation enhancer.Preferably, the polymeric analgesic reservoir material is an adhesivepolymer, which is solubilized in an organic solvent, e.g., ethanol,ethyl acetate, hexane, and the like. The mixer is then closed andactivated for a period of time to achieve acceptable uniformity of theingredients. The mixer is attached by means of connectors to a suitablecasting die located at one end of a casting/film drying line. The mixeris pressurized using nitrogen to feed solution to the casting die.Solution is cast as a wet film onto a moving siliconized polyester web.The web is drawn through the lines and a series of ovens are used toevaporate the casting solvent to acceptable residual limits. The driedanalgesic reservoir film is then laminated to a selected barrier and thelaminate is wound onto the take-up rolls. In another process, theanalgesic reservoir can be formed using dry-blending and thermalfilm-forming using equipment known in the art. Preferably, the materialsare dry blended and extruded using a slot die followed by calendaring toan appropriate thickness. Parameters such as analgesic loading,analgesic reservoir thickness, analgesic selections, material selectionsand manufacturing process can be varied for preparing analgesicreservoirs of the current invention, as illustrated in the Exampleshereinafter.

Transdermal Analgesic System

In subsequent operations, the analgesic reservoir containingintermediate and the antagonist reservoir containing intermediate arelaminated and the individual transdermal systems are die-cut, separatedand unit-packaged using suitable pouchstock. The antagonist reservoircontaining intermediate may be laminated immediately after drying theanalgesic reservoir containing intermediate. Transdermal analgesicsystems are cartoned using conventional equipment.

Experimental

Below are examples of specific embodiments for carrying out the presentinvention. The examples are offered for illustrative purposes only, andare not intended to limit the scope of the present invention in any way.

Efforts have been made to ensure accuracy with respect to numbers used(e.g., amounts, temperatures, etc.), but some experimental error anddeviation should, of course, be allowed for.

Specific examples of various transdermal analgesic systems of theinvention which are capable of administering fentanyl and analogsthereof for extended periods of time will be described in the examplesset for hereinafter. The transdermal analgesic systems compriseanalgesic reservoirs comprising an analgesic at concentration greaterthan, equal to, or less than saturation concentration. Theadhesive-analgesic reservoir systems wherein the analgesic reservoircomprises a single phase formulation of free undissolved componentscontaining an amount of fentanyl at subsaturation concentration arepresently considered preferable according to our invention. In thefollowing examples all percentages are by weight unless noted otherwise.

Example 1

Monolithic transdermal analgesic reservoirs according to FIG. 1 wereprepared containing 1.5 mg/cm² of fentanyl base. A polacrylate adhesive(National Starch 87-2287, 100 g) was solubilized in a solvent (ethylacetate, 128 ml). Fentanyl base was added to the polacrylate adhesivesolution in amounts sufficient to generate a mixture containing 4 wt %of fentanyl in the adhesive solution and stirred to dissolve theanalgesic. The solution was cast on to a peelable protective liner suchas a siliconized polyester film, and the solvent was evaporated toprovide a 0.05 mm (2 mil) thick reservoir layer.

Similarly, monolithic transdermal analgesic reservoirs were preparedusing the polacrylate adhesive (National Starch 87-4287, 100 g), asdescribed above.

Example 2

Monolithic transdermal analgesic reservoirs were prepared as describedin Example 1 with the following exceptions. Materials were dry blended,in the absence of ethyl acetate, and extruded using a slot die followedby calendaring to an appropriate thickness.

Example 3

Monolithic transdermal analgesic reservoirs according to FIG. 1 wereprepared as follows. A polacrylate adhesive (National Starch 87-2287,500 g) and glyceryl monolaurate (GML, 10 g) were dissolved in a solvent(ethyl acetate, 640 ml). Fentanyl base was added to the polacrylateadhesive solution in amounts sufficient to generate a mixture containing4 wt % of fentanyl in the adhesive solution and stirred to dissolve theanalgesic. The solution was cast on to a peelable protective liner suchas a siliconized polyester film and the solvent was evaporated toprovide a 0.045 mm (1.8 mil) thick reservoir layer. The analgesictransdermal systems contained 0.35 mg/cm² of fentanyl base.

Similarly, monolithic transdermal analgesic reservoirs are preparedusing the polacrylate adhesive (National Starch 87-4287, 100 g), asdescribed above.

Example 4

Monolithic transdermal analgesic reservoirs as described in Example 3with the following exceptions. Materials were dry blended, in theabsence of ethyl acetate, and extruded using a slot die followed bycalendaring to an appropriate thickness.

Example 5

Monolithic transdermal analgesic reservoirs were prepared comprisingrespectively, 0.25, 0.5, 0.75, 1.0 and 1.1 mg each of sufentanil, per2.54 cm², in a polacrylate adhesive (National Starch 87-4287, asdescribed in Example 1 above.

Similarly, monolithic transdermal analgesic reservoirs were preparedusing the polacrylate adhesive (National Starch 87-2287, 100 g), asdescribed above.

Example 6

Monolithic transdermal analgesic reservoirs were prepared containing,0.25, 0.5, 0.75, 1.0 and 1.1 mg each of sufentanil, and permeationenhancers (1 mg) comprising lauryl pyroglutamate, glycerol monolaurate,glycerol monocaprylate and glycerol monocaproate, respectively per 2.54cm² as described in Example 5.

Example 7

The transdermal analgesic reservoir described above in examples 1-6 waslaminated to the PET face of the PET/EVA barrier layer (for example asdepicted in FIG. 1) to provide a transdermal analgesic reservoircontaining intermediate.

Example 8

The transdermal analgesic reservoir described above in examples 1-6 iscoated with an adhesive coating followed by lamination to the PET faceof the PET/EVA barrier layer (for example as depicted in FIG. 3) toprovide a transdermal analgesic reservoir containing intermediate.

Example 9

The transdermal analgesic reservoir described above in examples 1-6 islaminated to an analgesic rate controlling membrane followed bylamination to the PET face of the PET/EVA barrier layer (for example asdepicted in FIG. 2) to provide a transdermal analgesic reservoircontaining intermediate.

Example 10

The transdermal analgesic reservoir described above in examples 1-6 islaminated to an analgesic rate controlling membrane. The skin proximatesurface of the analgesic rate controlling membrane is coated with anadhesive coating followed by lamination to the PET face of the PET/EVAbarrier layer (for example as depicted in FIG. 4) to provide atransdermal analgesic reservoir containing intermediate.

Example 11

Antagonist reservoir containing intermediates were prepared as follows.A thermoformable polymer (460 g), such as Engage® ethylene-octenecopolymer, (DuPont-Dow Elastomers, Midland, Mich.), was placed withinthe bowl of a high torque blender. The bowl was heated (150° C.) and thepolymer pellets were blended until the polymer pellets were sufficientlymasticated to provide a molten mass (10 minutes). The antagonist(naltrexone hydrochloride USP, 540 g) was added to the mixing bowl, andthe mixture was blended for about 30 minutes. The polymer melt wasemptied from the blending bowl and extruded between two moving webs: anupper layer of 0.05 mm (2 mil) polyester/EVA film (EVA side toward themelt) and a lower layer of 0.075 mm (3 mil) siliconized polyester film.The three-layer film structure was passed through calendar rolls to sizethe antagonist reservoir disposed on the barrier layer to about 0.025 mm(1 mil) thickness. The moving web was taken up in roll form at the endof the extrusion line.

In a second pass through the line, the siliconized interleaving wasremoved and a microporous polyethylene film (SOLUPOR, DSM Solutech,Heerlan, the Netherlands) was heat laminated to the exposed antagonistreservoir using a calendar. The microporous membrane provides theantagonist release controlling means for the final transdermal analgesicsystem. The resulting structure was taken up in roll form as anintermediate product comprising the antagonist reservoir disposed on theantagonist release controlling means or layer.

The antagonist reservoir containing intermediate described above waslaminated to the analgesic-containing adhesive film exiting the dryingovens described in examples 1-6 above, providing a six-layer filmlaminate: peelable liner, analgesic reservoir; optionally containing arate control membrane, barrier layer (polyester, EVA), antagonistreservoir (polyethyleneoctene-naltrexone HCl) and the antagonist releasecontrolling means (microporous polyethylene). The total film thicknesswas about 0.2 mm (8 mil).

The six-ply film was die-cut to individual transdermal analgesic systemscorresponding to analgesic delivery areas of 1 cm² to 44 cm². Infentanyl containing systems, the fentanyl to naltrexone loading ratio inthe final systems was 1:2, and the fentanyl delivery rates of about 12.5to about 100 μg/h depending upon the system area. In sufentanilcontaining systems, the sufentanil to naltrexone loading ratio in thefinal systems is 1:4-16, and the sufentanil delivery rates of about 1.5to about 12 μg/h depending upon the system area.

Example 12

Antagonist reservoir containing intermediates were prepared as follows.A thermoformable polymer (460 g), such as Engage® ethylene-octenecopolymer, (DuPont-Dow Elastomers, Midland, Mich.), was placed withinthe bowl of a high torque blender. The bowl was heated (150° C.) and thepolymer pellets were blended until the polymer pellets were sufficientlymasticated to provide a molten mass (10 minutes). The antagonist(naltrexone hydrochloride USP, 540 g) was added to the mixing bowl, andthe mixture was blended for about 30 minutes. The polymer melt wasemptied from the blending bowl and extruded between two moving webs: anupper layer of 0.075 mm (3 mil) fluoropolymer release liner film(fluorocarbon diacrylate coated polyester film), and a lower layer of0.075 mm (3 mil) siliconized polyester film. The three-layer filmstructure was passed through calendar rolls to size the antagonistreservoir disposed on the barrier layer to about 0.025 mm (1 mil)thickness. The moving web was taken up in roll form at the end of theextrusion line.

In a second pass through the line, one of the siliconized interleavingwas removed and a microporous polyethylene film (SoluPor, Solutech,Denmark) was heat laminated to the exposed antagonist reservoir using acalendar. The microporous membrane provides the antagonist releasecontrolling means for the final transdermal analgesic system. Theresulting structure was taken up in roll form as an intermediate productcomprising the antagonist reservoir.

In the third pass through the line, the siliconized interleaving wasremoved and an adhesive layer, was laminated to the exposed antagonistreservoir using a laminator, providing a four layer film laminate:adhesive layer, barrier layer, antagonist reservoir(polyethyleneoctene-naltrexone HCl) and antagonist release controllingmeans (microporous polyethylene). The four ply film was die cut toindividual units corresponding to form fill seal (FFS) system areas of10, 20, 30 and 40 cm².

Analgesic reservoir containing intermediates are prepared as follows.Fentanyl base (1.4 Kg) was slurried in purified water (5 L, USP) in avessel. Ethanol (25 Kg, USP) and water (65 L, USP) were mixed in a 40gallon pressure vessel, the solution was stirred, and allowed to cool toroom temperature. The fentanyl slurry was added to the ethanol solution,using water (4 L, USP) to rinse the vessel quantitatively. In a separatevessel, hydroxyethyl cellulose (2 Kg, QP 100,000 [HEC], NF) was slurriedwith water (4 L). The hydroxyethyl cellulose slurry was added withmixing to the fentanyl mixture in the 40 gallon mixer. The remaininghydroxyethyl cellulose was rinsed using water (2 L) and added to thelarge mixer vessel. The vessel was immediately stirred at 100cycles/minute until the analgesic reservoir mixtures gels.

The pressure vessel containing the fentanyl gel was attached to amulti-nozzle gel placement array mounted on a Bodolay Form-Fill-Sealing(FFS) machine. A laminate composed of the protective liner (peelablePET-silicone film), adhesive layer (silicone adhesive film, 1.57 mil),and analgesic release rate controlling means (an EVA film (9% VA), 2mil) was laid out onto the equipment used to build the form fill sealsystems. The analgesic reservoir was metered onto the protectiveliner/adhesive layer/analgesic release rate controlling means such thatthe gel contacted the analgesic release rate controlling means. Thebarrier layer (PET/EVA) was laid out such that it covered the gel. TheEVA component of the barrier layer contacted the analgesic releasecontrolling membrane. The perimeter of the construction was heatlaminated, forming the analgesic portion of the system formingperipherally sealed systems with 245 mg of reservoir gel per 10 cm²system active drug release area. The film was die cut to individualunits corresponding to analgesic delivery areas of 10 to 40 cm² to formthe analgesic reservoir containing intermediate.

The adhesive surface of the antagonist reservoir containing intermediateis laminated onto the barrier layer of the analgesic reservoircontaining intermediate to form the transdermal analgesic system havinga form fill seal (FFS) analgesic reservoir.

In fentanyl containing systems, the fentanyl to naltrexone loading ratioin the final systems is 0.5 to 4, and the fentanyl delivery rates ofabout 12.5 to about 100 μg/h depending on the system area.

Example 13

The antagonist reservoir containing intermediate described in Example 11is laminated to the analgesic reservoir described in Examples 9 and 10above, providing a eight-layer film laminate: peelable liner, adhesivelayer, analgesic rate control membrane, analgesic reservoir(analgesic-adhesive layer), barrier layer (polyester, EVA), antagonistreservoir (polyethyleneoctene-naltrexone HCl) and antagonist releasecontrolling means (microporous polyethylene).

The eight-ply film is die-cut to individual transdermal analgesicsystems corresponding to analgesic delivery areas of 5.5 to 44 cm². Infentanyl containing systems, the fentanyl to naltrexone loading ratio inthe final systems is 1:2, and the fentanyl delivery rates of about 12.5to about 100 μg/h depending upon the system area. In sufentanilcontaining systems, the sufentanil to naltrexone loading ratio in thefinal systems is 1:4-16, and the sufentanil delivery rates of about 1.5to about 12 μg/h depending upon the system area.

Example 14

A thermoformable polymer, polyolefin elastomer (460 g), such as Engage®ethylene-octene copolymer, (DuPont-Dow Elastomers, Midland, Mich.), wasmelt blended (88-100° C.) with naltrexone hydrochloride dihydrate (690g) for about 1.5 to 2.5 hours. The mixture was extruded betweendifferential release liners, calendared to a thickness of 0.025 mm (1mil) to form an antagonist reservoir. The antagonist reservoir waslaminated to the PE face of a PET-PE barrier film (Mediflex 1203, Mylan,St. Albans, Vt.), at 0-100° C., 71 psig, 4 ft/min. The remaining releaseliner was removed and the barrier layers were laminated at 60° C., 38psig, 4 ft/min. The antagonist release rate controlling means, e.g.,Solupor 10PO5A, Pluronic-modified Solupor, Celgard microporouspolypropylene (Grades 3401 and 3501), spun-bonded polypropylene, andpolyethylene film were laminated to the antagonist reservoir between 60and 90 psig, 4 ft/min.

The PET face of the antagonist reservoir containing intermediatedescribed above was laminated to the analgesic-containing adhesive filmexiting the drying ovens described in Examples 1-6 above, at 24 ft/min,25° C., 70 psig. The liner was replaced with a slit release liner toenable easy system removal from the liner, and die cut to the desireddimensions, 5.5 to 44 cm².

Example 15

A thermoformable polymer, such as Elvax® 210 ethylene-vinyl acetatecopolymer (1.61 Kg, 28% vinyl acetate, E.I. DuPont de Nemours,Wilmington, Del.), was melt blended (77-88° C.) with naltrexonehydrochloride dihydrate (1.89 Kg) for about 1.5 to 2.5 hours. Themixture was extruded between differential release liners, and calendared(0.031 mm) to form an antagonist reservoir. The antagonist reservoir waslaminated to the EVA face of a PET-EVA barrier film (Scotchpac 9733, 3M,Minneapolis, Minn.), at 80-85° C., 70-90 psig, 4-19 ft/min. Theremaining release liner was removed and the antagonist release ratecontrolling means, microporous polyethylene (e.g., Solupor 10PO5A, orPluronic-modified Solupor,) was laminated to the antagonist reservoirbetween 80-85° C., 50-54 psig, 4-24 ft/min.

The PET face of the antagonist reservoir containing intermediatedescribed above was laminated to the analgesic-containing adhesive filmexiting the drying ovens described in Examples 1-6 above, at 24 ft/min,25° C., 70 psig. The liner was replaced with a slit release liner toenable easy system removal from the liner, and die cut to individualtransdermal analgesic systems corresponding to analgesic delivery areasof 5.25 to 44 cm².

Example 16

The antagonist reservoir containing intermediate described in theExamples above was prepared with the following exceptions. Antagonistrelease controlling means were prepared as follows, Pluronic F108NFsolutions (0.5, 1.0, and 2.0 wt %) were prepared in a solvent (3% water:97% ethanol). The Solupor material 10PO5A was coated with the Pluronicsolutions and dried at room temperature overnight, providing coatingweights of 35 μg/cm², 50 μg/cm², and 90 μg/cm² for the 0.5, 1.0, and 2.0wt % Pluronic solutions, respectively. These antagonist releasecontrolling means, i.e. surfactant-modified membranes were laminated tothe antagonist reservoir as described in the previous examples.

Example 17

The antagonist reservoir containing intermediate described in theExamples above is prepared with the following exceptions. Antagonistrelease controlling means (a salt-filled membrane which forms pores insitu upon exposure to water) is prepared as follows. Ethylene-vinylacetate copolymer (EVA) with 28% vinyl acetate monomer (Elvax 210, E.I.DuPont de Nemours, Wilmington, Del.) is added to the hopper of acryogrinder (10 Kg). The cryogrinder is then filled to the mark withliquid nitrogen and the top is sealed. The grinder is activated forabout 10 minutes and the polymer pellets are comminuted to an averageparticle size of about 0.05 mm, and dried (using a stream of warm air)to obtain the ground polymer.

Powdered sodium chloride, with approximately 2% magnesium sulfate,(National Formulary, about 10 Kg) is added to the hopper of a V-blender.The ground polymer (10 Kg) is then added to the hopper. The hopper isactivated to rotate for approximately 15 minutes, to obtain a powderblend that is a consistent mixture of polymer and sodium chloride.

The powder blend is continuously fed to the addition-port of asingle-screw extruder, the heating sections of which are pre-warmed toapproximately 110° C. At the end of the extruder, a flex-nip die isattached which has been set to an exit thickness of about 0.25 mm (10mil). The extruder is operated to produce film that is fed to the rollsof a three-roll calendar. The roll-nip is set to produce a continuousfilm exiting the calendar that is about 0.03 mm (1.5 mil) thick. Thisfilm is wound on take-up rolls for further manufacturing use.

These antagonist release controlling means, i.e. salt-containing filmare laminated to the antagonist reservoir as described in the previousexamples. Final systems are die-cut and packaged. Upon immersion of suchsystems in water, the sodium chloride layer rapidly desorbs thewater-soluble salt. The resulting film forms an in situ microporousmembrane that provides a release rate ratio of the antagonist to theanalgesic of least 2:1 and up to 20:1.

Example 18

The antagonist reservoir containing intermediates as described inExamples 11-17 are manufactured using an alternative continuous process.A gravimetric or volumetric feeder is used to feed thermoplastic polymerinto a twin screw extruder, reciprocating single screw extruder(“co-kneader”) or continuous compounder. The antagonist is fed in a likemanner into the melted polymer and mixed, and extruded into a calendarinto the intermediate antagonist reservoir laminate. Alternatively, themixture is extruded into a strand or rod, cut into pellets(approximately 5-10 mm) and subsequently extruded in a second step.

Example 19

The antagonist intermediate containing reservoir described in Examples11-18 is prepared with the following exception. The intermediateantagonist reservoir is extrusion coated directly to the EVA face of thebarrier layer on a chill roll and the antagonist rate controlling layeris laminated in the same process step.

Example 20

The systems manufactured according to Examples 11-19 were used to studythe release of naltrexone from the system upon immersion in water atambient temperature, i.e. room temperature. The transdermal analgesicsystems were immersed in distilled water. After selected time intervals,the systems were moved to fresh extraction media. This operation wasrepeated for a total time of 24 hours. The naltrexone released duringthis test procedure matched the rate and extent of the fentanyl releasedas determined after performing a similar test procedure to measureopioid release. These systems released naltrexone to fentanyl at a ratioof 2:1 over at least a one-hour period of immersion in water.

Example 21

The systems manufactured according to Examples 11-20 were used to studythe release of naltrexone from the system upon immersion in a bufferedaqueous medium containing phosphate buffer at pH 6.5 at ambienttemperature, i.e. room temperature or at boiling temperature. The volumeof the medium was adjusted to be below the solubility limit of theantagonist and the analgesic.

The release rate of antagonist into phosphate buffered medium iscontrolled by membrane selection or surfactant modification of theantagonist release controlling means. FIGS. 6-16 illustrate release rateprofiles for various transdermal analgesic systems described in theExamples above. FIGS. 6, 7 and 8 illustrate the cumulative release ofnaltrexone from a Pluronic coated Solupor antagonist release controllingmeans. FIGS. 9 and 10 illustrate release rate and cumulative release ofnaltrexone, respectively, from a Celgard 3401 antagonist releasecontrolling means. FIGS. 11 and 12 illustrate release rate andcumulative release of naltrexone, respectively, from an impermeable LDPEantagonist release controlling means. FIGS. 13 and 14 illustrate releaserate and cumulative release of naltrexone, respectively, from a Celgard3501 antagonist release controlling means. FIGS. 15 and 16 illustraterelease rate and cumulative release of naltrexone, respectively, from aspun bonded polypropylene antagonist release controlling means. Each ofFIG. 9-16 illustrates data from triplicate experiments (#1, 2 and 3) andthe average data.

Example 22 Extraction Studies

An unused, intact transdermal analgesic system (100 μg/h, 42 cm²) wasplaced into standard extraction medium/solution (approximately 300 mL)equilibrated to the target temperature. Examples of standard extractionmedium used include common household materials such as distilled water,vodka, rubbing alcohol, cooking oil, vinegar/water mixture and acetone.Aliquot of the extraction medium (1 mL) was removed at 0, 2, 5, 15, 60and 120 minutes and diluted with unused extraction medium (5 mL). Thesamples were assayed for naltrexone and fentanyl content by HPLC.Extractions were conducted at 25° C. and repeated at 50° C. and 75° C.(where possible). The release rate ratio of antagonist to analgesicranged from about less than 0.1:1 to about 3.6:1.

Example 23

Transdermal systems fabricated in Example 11 were adhered to a sectionof human epidermis that had been previously excised from the underlyingdermis tissue using techniques known to those skilled in the art. Thesystem/skin sandwich was placed in a Franz diffusion cell. The number ofreplicate samples was 12. The entire apparatus was immersed within awater bath thermostatted to 32° C. The receptor compartment of the cellwas filled with aqueous phosphate buffer at pH 6.5. The receptorcompartment was sampled at selected intervals over a three-day period.The solutions were assayed for fentanyl and naltrexone using sensitiveHPLC assay techniques. Using the fentanyl/naltrexone concentration,diffusion area, sample volume and sampling time interval, thefentanyl/naltrexone flux was calculated. The results showed that after atransient start-up period, the mean flux of fentanyl was about 2μg/h-cm², while the naltrexone flux was a value below the detectionlimit of the assay (i.e. <<0.1 μg/h-cm²).

Example 24 Sensitization Studies

Systems were prepared as follows:

Male hairless guinea pigs (Charles River Laboratories, Boston, Mass.)were used to assess the sensitization potential of a 48-hour dermalapplication of a transdermal system (2.5 cm²). The transdermal systemwas composed of a skin adhesive (NS Duro-Tak 87-2287 or NS Duro-Tak87-4287), a barrier film, a polymer with (transdermal analgesic system)and without (transdermal placebo system) naltrexone HCl, and a porousbacking layer. Guinea pigs were divided into the following six groups:

TABLE 1 Group N Induction Treatment and Challenge Treatments 1 5Induction Treatment: Transdermal placebo system (2287 adhesive)Challenge Treatments: Transdermal placebo system (2287 adhesive)Transdermal analgesic system (2287 adhesive) 2 5 Induction Treatment:Transdermal placebo system (4287 adhesive) Challenge Treatments:Transdermal placebo system (4287 adhesive) Transdermal analgesic system(4287 adhesive) 3 10 Induction Treatment: Transdermal placebo system(2287 adhesive) Challenge Treatments: Transdermal placebo system (2287adhesive) Transdermal analgesic system (2287 adhesive) 4 10 InductionTreatment: Transdermal placebo system (4287 adhesive) ChallengeTreatments: Transdermal placebo system (4287 adhesive) Transdermalanalgesic system (4287 adhesive) 5 5 Induction Treatment: 0.05% (w/v)1-chloro 2-4dinitro benzene (DNCB) in acetone (positive control)Challenge Treatments: Acetone 0.05% DNCB 6 5 Naïve Control ^(a) Nominalconcentration of naltrexone HCl per system = 3.44 mg

During the induction period, animals in Groups 1-5 received nine topicalinductions to the dorsal skin area over 21 days (3 applications perweek) of their respective test or control articles. Each application wasworn for approximately 48 hours except for DNCB (positive control),which was worn for 24 hours. Prior to each dermal application and aftersystem removal, the skin sites were wiped with an alcohol swab andblotted dry with a gauze pad. The margins of the skin application siteswere marked with a skin-marking pen after system removal. For Groups1-4, sites were evaluated for skin irritation 2±0.5 hours after systemremoval for the first induction, and 2±0.5 and 24±1 hours after systemremoval for the last induction. For Group 5, after removal of the firstand last induction applications, sites were evaluated for primary andcumulative skin irritation, respectively, 2±0.5 and 24±1 hours aftersystem removal.

Within approximately 10 to 14 days after the last induction application,each guinea pig was challenged according to the treatment presented inthe table. Each topical application was worn for approximately 48 hoursexcept for DNCB (positive control), which was worn for 24 hours. Allapplication sites were scored for irritation approximately 2±0.5, 24±1,and 48±1 hours after removal of the challenge article. All scoring wasconducted using a modified Draize scale (0-4 for erythema and 0-4 foredema). Responses were defined as positive for sensitization if thecombined erythema and edema scores were ≧2 at 48 hours after challenge.

The mean irritation scores for the systems with the transdermalantagonist system (2287 adhesive) after the first and last inductionapplications were similar with no evidence of cumulative irritation andcategorized the transdermal system as a mild irritant. The meanirritation scores for the transdermal antagonist system (4287 adhesive)after the first and last induction applications were similar with noevidence of cumulative irritation and categorized the transdermal systemas a low-moderate irritant.

No evidence of sensitization was observed in any of the guinea pigsinduced and challenged with the transdermal placebo system ortransdermal antagonist system. This categorizes the transdermal systemsas having a weak sensitization potential. A sensitization response waselicited in all of the guinea pigs induced and challenged with thepositive control, DNCB, confirming that a response can be elicited inthis model.

The manufacturer of the skin acrylate adhesives has also conductedsafety tests on each adhesive, including a Buehler sensitization study.The data support the safe use of each adhesive.

A GLP study conducted in conscious hairless guinea pigs revealedintradermally injected or topically applied naltrexone gel as having amoderate to strong contact sensitization potential under the conditionsof the study. A second GLP study was conducted in conscious hairlessguinea pigs with transdermal placebo and antagonist systems. No evidenceof sensitization was observed in any of the guinea pigs induced andchallenged with the transdermal placebo systems or the transdermalantagonist systems. This categorizes the transdermal systems as having aweak sensitization potential. A sensitization response was elicited inall of the guinea pigs induced and challenged with the positive control,DNCB, confirming that a response can be elicited in this model (studydetails are presented below). Additional safety data on the skinacrylate adhesives used in these studies are available from themanufacturer. The data support the safe use in a clinical sensitizationstudy of the transdermal systems with and without naltrexone in thebacking.

Example 25 Skin Irritation Study

A GLP skin irritation study was conducted in conscious male hairlessguinea pigs (strain IAF:HA-HO-hr) to evaluate the irritation potentialof various sufentanil containing transdermal analgesic systems after asingle 72-hour topical application. Two transdermal systems (having athickness of 0.025 mm (1.0 mil) and 0.05 mm (2.0 mil)) composed of askin adhesive (NS Duro-Tak 87-4287) containing sufentanil base, and abacking layer were tested (as described in Example 11). The in vitroflux of sufentanil base from both systems was approximately 0.60μg/cm²/hr. Each of the six guinea pigs had one system of each thicknessapplied to intact dorsal skin areas for 72 (±1) hours. The sites werescored for erythema, eschar, and edema at 30-40 minutes, 24 (±1), and 48(±1) hours after the test articles were removed. Each application sitewas scored, using the Draize scale of 0-4 for erythema and 0-4 foredema. Primary Irritation Indices (PIIs) were calculated.

Mild irritation was observed after application of all systems. Nochanges in clinical condition occurred. The systems can be used in asingle application human clinical study with a wearing period of up to72 hours.

Example 26

Yucatan miniature swine were used to assess potential systemic toxicityfollowing the intra-oral administration of a transdermal analgesicsystem. The transdermal system was composed of a skin adhesive (NSDuro-Tak 87-4287) with fentanyl, a barrier film, a polymer withnaltrexone HCl, and a porous backing layer (as described in Example 14).The transdermal analgesic systems, with naltrexone HCl in the backing,contained approximately 8.8 mg of fentanyl per system and 35.2 mg ofnaltrexone HCl (0.4 mg/cm², in a 22 cm² system).

Healthy female Yucatan miniature swine, obtained from S&S Farms(Ranchita, Calif.), weighing 19-27 kg, and at least 6 months old, wereused. The swine were identified by ear notches. Five animals weresedated and anesthetized with approximately 4 mg/kg of Telazol® andIsoflurane (for ear cannulation), respectively, and the systems wereplaced in their oral cavities for 11-30 minutes. Anesthesia wasdiscontinued and the animals were allowed to recover. The animals wereclosely monitored for clinical signs.

The transdermal analgesic systems were removed from the oral cavity andallowed to air dry. Residual drug analysis was performed on all fivetransdermal antagonist systems administered. As tabulated in Table 2,both the fentanyl and the naltrexone were released out of the patch intothe oral cavity. The release rate ratio of naltrexone to fentanyl wasapproximately about 6:1 to about 8:1. No fentanyl toxicity was observedin four out of the five animals dosed.

TABLE 2 Swine dosed with transdermal antagonist system Total Amount ofAmount of Release Exposure Naltrexone fentanyl rate Ratio Ani- WeightTime delivered delivered of Nal- mal (kg) (min) (mg) (mg)trexone:Fentanyl 1 20.3 30 12.3 1.52 8:1 2 22.3 11 5.12 0.81 6:1 3 27.526 10.9 1.32 8:1 4 19.8 27 8.24 1.28 6:1 5 23 20 10.78 1.38 8:1

Example 27 Sufentanil/Naltrexone Ratio Study in Rats

Groups of male rats (CRL:CD® (SD) IGSBR) were administered the followingtest agents intravenously via a tail vein: naltrexone hydrochloridealone, sufentanil alone, or naltrexone hydrochloride followedimmediately by sufentanil. The objective of the study was to determinedoses of naltrexone that would effectively antagonize the severe opioideffect profile induced by a pre-selected intravenous dose of sufentanil(18.75 μg/kg). The dose groups are summarized in the table below.

TABLE 3 Naltrexone/Sufentanil Naltrexone¹ Sufentanil¹ Ratio Number ofRats — 18.75 NA 8 300 — NA 3 300 18.75 16:1  4 150 18.75 8:1 4 75 18.754:1 4 18.75 18.75 1:1 4 ¹= (μg/kg iv)

Following injection of test agents, animals were observed for clinicalsigns. Naltrexone was effective in blocking opioid-induced effects ofsufentanil at naltrexone: sufentanil dose ratios of 4:1, 8:1, and 16:1.Duration of naltrexone antagonism was comparable at each of the threedose ratios and appeared to last as long as clinical signs persisted inthe sufentanil control group (generally 1-2 hours). The 1:1naltrexone:sufentanil dose ratio was less effective in blockingsufentanil-induced clinical signs, but at this dose ratio clinical signswere generally less severe and shorter lasting than in the sufentanilcontrol group. Naltrexone (300 μg/kg) administered alone to rats (N=3)produced no apparent effects. FIGS. 17 and 18 illustrate the effect ofnaltrexone on sufentanil-induced clinical signs in rats (within 30minutes after dosing).

Example 28 Evaluation of the Contact Sensitization Potential TransdermalSystems in Healthy Subjects

The contact sensitization potential of the components of transdermalanalgesic system in healthy subjects were conducted using varioustransdermal antagonist patches as described in Example 11 above: SystemA: transdermal analgesic system (placebo) with naltrexone (44 cm²); andSystem B: transdermal analgesic system (placebo) (44 cm²). A secondaryobjective was to demonstrate non-quantifiable serum naltrexoneconcentrations.

The study was a single center, double blind, randomized study withInduction, Rest, and Challenge Phases. In the present study, 240subjects received system A and 80 subjects received system B. System A(transdermal placebo analgesic system with naltrexone) contains apolyester release liner, a polyacrylate adhesive, and a polyesterbacking laminated to a polyethylene film with a naltrexone-polyethylenelayer. System B (transdermal placebo analgesic system withoutnaltrexone) contains a polyester release liner, a polyacrylate adhesive,and a polyester backing laminated to a polyethylene film with apolyethylene layer.

During the Induction Phase, each subject received either system A orsystem B, for a total of nine consecutive systems applied to the sameskin site over a total of 21 days. If the application site had to bechanged due to severe skin reactions from a previous system application,a different site on the same arm was used to continue with the 21-dayapplication plan. Each system was worn continuously for two or threedays (48 or 72 hours)±4 hours. The system was applied to skin sites onthe upper outer arm. Immediately following removal of each InductionPhase system, and 24 hours after the removal of the last Induction Phasesystem, the application site was assessed for topical reactions using astandard grading scale.

During the Rest Phase, which commenced after the Induction Phase, therewas no application for two weeks. During the Challenge Phase, whichcommenced after the Rest Phase, two systems (one A and one B) wereapplied to naive skin sites on the upper outer arm not used in theInduction Phase and worn for 48 hours. After removal of the ChallengePhase transdermal analgesic systems, the skin sites were assessed fortopical irritation and sensitization reactions at 0.5, 24, 48, and 72hours after removal. Any questionable sensitization reaction wasconfirmed by a re-challenge that was applied to new sites 24 hours afterremoval of the first Challenge Phase systems. Two systems (one A and oneB) were applied to naive skin sites on the upper outer arm not used inthe Induction Phase (or on upper chest if necessary) at the 24-hourassessment of the first challenge and worn for 48 hours. They wereremoved and follow-up assessments were performed at 0.5, 24, 48, and 72hours post-removal. Following removal of each Induction Phase system,the application site was assessed for topical reactions and adherence,using standard grading scales.

Blood samples were drawn for analysis of naltrexone concentrationsbefore system application on day 1 and before the removal of the systemon days 17, 19, and 22. The serum was removed from the blood samplesusing standard procedures. Serum samples were analyzed using a validatedliquid chromatography-tandem mass spectrometry (LC/MS/MS) method. Thelower limit of quantitation was approximately 5 pg/mL.

The transdermal analgesic systems demonstrated acceptable levels ofadhesion and irritation. No evidence of sensitization was observed. Thenaltrexone concentration in majority of the serum samples was belowquantifiable limits. Accordingly, there was no evidence of systemicadministration of naltrexone.

Example 29 Activity Studies

The primary objective of this study was to evaluate serum naltrexoneconcentrations following application of a transdermal analgesic placebosystem with naltrexone system under various conditions (normal activity,showering and physical exercise).

The secondary objective was to evaluate residual naltrexone in the usedsystems following a 4 hour wear period under various conditions (normalactivity, showering and physical exercise).

The study was a randomized, single-center, open-label, three 4-hourperiod, two-sequence crossover study. Subjects were randomly assigned toone of two treatment sequences. All three periods took place on the sameday. During each period, each subject wore one new transdermal analgesicplacebo system with naltrexone (44 cm²) system for 4 hours and engagedin normal activity; strenuous physical activity (20 minutes, roomtemperature), or take a warm shower (10 minutes at approximately 40°C.). The normal activity was first while the order of the other twoactivities was randomized.

Blood samples were collected for determination of serum naltrexoneconcentrations before the first system application, then at 2, 4, 5, 6,7, 8, 9, 10, 11, 12, 13 hours following system application. During theexercise and shower activities, an additional blood sample was takenfollowing the completion of the activity. Serum samples were analyzedfor determination of naltrexone concentration using a validated liquidchromatography-tandem mass spectrometry (LC/MS/MS) method. The lowerlimit of quantitation was approximately 5 pg/mL.

The adherence of each transdermal analgesic system was assessed justprior to removal of the system. Each skin site to which a system wasapplied was monitored for topical reactions (including erythema, edema,pustules, papules and itching) approximately 15 minutes, one hour, and16-24 hours after removal.

The residual naltrexone in the used systems was measured after thesystem was removed. The analysis method for naltrexone in used systemswas preformed as follows. The systems were first weighed, removed fromthe protective liner and placed onto nylon netting, then rolled andplaced into the extraction vessel. Extraction was performed using anorganic solvent with shaking, followed by dilution with an organicsolvent/water mixture. The naltrexone was measured using reversed-phaseHPLC with UV detection.

The percent loss of naltrexone content from the transdermal systemaveraged about 2-3% during normal and strenuous physical activity.During the showering activity, the percent loss of naltrexone contentfrom the transdermal system averaged about 23%. The naltrexoneconcentration in majority of the serum samples was below quantifiablelimits. Accordingly, there was no evidence of systemic administration ofnaltrexone. Additionally, the transdermal analgesic systems demonstratedacceptable levels of adhesion and irritation. No evidence ofsensitization was observed.

Example 30 Bioequivalence Study

The in vivo fentanyl flux studies were conducted using varioustransdermal fentanyl systems—transdermal analgesic system as describedin Example 14, and DUROGESIC™ fentanyl system, and the comparativepharmacokinetic parameters are tabulated in Table 4 and 5 below. Thepharmacokinetic parameters of the transdermal analgesic systems wereevaluated as follows.

A single-center, randomized, single-application, open-label,two-treatment, two-sequence, two-period, cross-over study usingtransdermal systems, each for 72 hour application: Treatment Durogesic™50 μg/h; and Treatment B (transdermal fentanyl system with naltrexone(50 μg/h of fentanyl) was performed to evaluate the pharmacokinetics ofthe systems after single application.

Subjects were randomly assigned to one of two treatment sequences (atleast 14 subjects per treatment sequence). Subjects wore two transdermalfentanyl systems sequentially over two 72-hour wearing periods on a skinsite on the upper outer arm. There was a minimum washout period of atleast 14 days and not more than 21 days between treatments. The washoutperiod commenced upon removal of the study system. The study system wasworn for 72 hours. Each subject received a bolus naloxone (0.5 mg)followed by continuous naloxone infusion (0.2 mg/h) as the opioidantagonist starting 15 minutes prior to system application and duringapplication and through 4 hours post system removal. Each subject thenreceived naltrexone 50 mg tablets at 6 and 20 hours post system removal.

At scheduled time points for both treatments (pre-dose and 2, 3, 5, 8,12, 18, 24, 30, 36, 42, 48, 54, 60, 66, 72, 73, 74, 76, 80, 84, 96, 108,and 120 hours following system application), blood samples werecollected from each subject for determination of serum fentanylconcentrations. Serum samples were analyzed for determination offentanyl concentration using a validated liquid chromatography-tandemmass spectrometry (LC/MS/MS) method. Topical skin irritation and systemadhesion were assessed at scheduled time points.

The results of the in vivo study are tabulated in Tables 4 and 5. FIG.19 illustrates serum fentanyl concentrations following transdermalapplication of various fentanyl systems—one application of transdermalanalgesic system of the invention (50 μg/h, 22 cm²); and DUROGESIC™fentanyl system (50 μg/h, 20 cm²), up to 120 hours after firstadministration.

Descriptive statistics were calculated for fentanyl pharmacokineticparameters for each treatment. Characteristics of theseconcentration-time curves, such as the area under the serum drugconcentration-time curve (AUC), time to maximum concentration (T_(max)),and the peak blood, plasma or serum concentration (C_(max)) of the drug,were examined by statistical procedures as described earlier. Amixed-effect analysis of variance (ANOVA) model which includestreatment, period, sequence, fixed effects and subject-within-sequencerandom effect was used for the analysis of fentanyl pharmacokineticparameters (log transformed AUC_(inf) and C_(max), Statistical methodsfor average bioavailability. (Design and Analysis of Bioavailability andBioequivalence Studies. S. Chow and J. Liu (eds), Marcel Dekker, NewYork, N.Y., 1992, pp 70-125). The ratios of the least square estimate ofthe mean parameters and their 90% confidence intervals (Schuirmann D.J., A comparison of the two one-sided tests procedure and the powerapproach for assessing the equivalence of average bioavailability; J.Pharmacokinet. Biopharm. 1987, 15: 657-680) were calculated. The lowerand upper bounds of the 90% confidence intervals were compared to 80%and 125%, respectively. A non-parametric Wilcoxon rank-sum test wasperformed on both fentanyl T_(max) and fentanyl fractional cumulativeAUCs. A significance level of 0.05 was used for these tests. The testand the reference formulation/composition were considered bioequivalentif the confidence interval around the ratio of the mean (test/referenceproduct i.e. Treatment A/Treatment B) value for a pharmacokineticparameter is no less than 80% on the lower end and no more than 125% onthe upper end. The results of the statistical analysis of logtransformed pharmacokinetic (PK) parameters are tabulated in Tables 4and 5.

TABLE 4 A Comparative Pharmacokinetic (PK) Parameters for transdermalfentanyl containing analgesic system and DUROGESIC ™ fentanyl systemStandardized Normalized Size Fentanyl C_(max) C_(max) (ng/ml- C_(max)(ng/ml- Dose (μg/h) (cm²) content (mg) (ng/ml) cm²) (mg/h)) DUROGESIC ™25 10 2.5 0.6 0.06 24 50 20 5.0 1.4 0.07 28 75 30 7.5 1.7 0.05 22.7 10040 10.0 2.5 0.06 25 Transdermal fentanyl systems 12.5 5.5 2.2 0.29 0.05223 25 11 4.4 0.58 0.052 23 50 22 8.8 1.15 0.052 23 75 33 13.2 1.73 0.05223 100 44 17.6 2.30 0.052 23 B Mean (CV %^(a)) pharmacokineticparameters for Transdermal Fentanyl Systems Treatment A (n = 26)Treatment B (n = 26) Fentanyl PK DUROGESIC ™ containing analgesic systemParameter (50 μg/h, 20 cm²) (50 μg/h, 22 cm²) C_(max) (ng/mL) 1.15 (36)1.25 (55) T_(max) (h) 39.0 (36) 40.1 (52) AUC₀₋₁₂₀ 63.5 (36) 75.3 (60)(ng/mL · h) AUC_(inf) 68.7 (41) 81.4 (62) (ng/mL · h) Half-life (h) 22.2(36) 22.2 (36) ^(a)= percent coefficient of variation

TABLE 5 Bioequivalence analysis of pharmacokinetic parameters (n = 26)90% confidence interval PK Parameter Ratio (%) Lower Upper Ln C_(max)101.84 92.37 112.28 Ln AUC_(inf) 110.27 102.61 118.51 Contrast is forTreatment B/Treatment A

Thus, as evidenced from the results tabulated above and illustrated inFIG. 19, the transdermal fentanyl containing analgesic systems of thepresent invention comprising naltrexone, are bioequivalent products tothe rate-controlled, saturated DUROGESIC™ fentanyl system. Inparticular, the transdermal analgesic system according to the inventiondisplay pharmacokinetic dynamic parameters comparable to the transdermalDUROGESIC™ fentanyl system: the 90% confidence interval for the averagelog transformed C_(max) and average ratios of the test formulationversus the reference formulation fell within the 80% to 120% range.

Example 31

The in vivo fentanyl flux studies were conducted using varioustransdermal fentanyl systems—transdermal antagonist system as describedin Example 15, and DUROGESIC™ fentanyl system, with the followingexceptions.

The serum samples collected at and before 76 hours post-application werealso analyzed for naltrexone concentration (Treatment B) using avalidated liquid chromatography-tandem mass spectrometry (LC/MS/MS)method.

TABLE 6 A Comparative Pharmacokinetic (PK) Parameters for transdermalfentanyl containing analgesic system and DUROGESIC ™ fentanyl systemStandardized Normalized Size Fentanyl C_(max) C_(max) (ng/ml- C_(max)(ng/ml- Dose (μg/h) (cm²) content (mg) (ng/ml) cm²) (mg/h)) DUROGESIC ™25 10 2.5 0.6 0.06 24 50 20 5.0 1.4 0.07 28 75 30 7.5 1.7 0.05 22.7 10040 10.0 2.5 0.06 25 Transdermal fentanyl systems 12.5 5.25 2.1 0.290.054 22.6 25 10.5 4.2 0.57 0.054 22.6 50 21 8.4 1.13 0.054 22.6 75 31.512.6 1.70 0.054 22.6 100 42 16.8 2.26 0.054 22.6 B Summary of mean (CV%^(a)) pharmacokinetic parameters Treatment A (n = 28) Treatment B (n =28) PK DUROGESIC ™ Fentanyl containing analgesic Parameter (100 μg/h, 40cm²) system (100 μg/h, 42 cm²) C_(max) (ng/mL) 2.26 (36) 2.47 (47)T_(max) (h) 48 (40) 37.6 (57) AUC₀₋₁₂₀ 133.7 (24) 143.5 (26) (ng/mL · h)AUC_(inf) 143 (26) 158.6 (28) (ng/mL · h) Half-life (h) 19.4 (22) 26.7(131) ^(a)= percent coefficient of variation

TABLE 7 Bioequivalence analysis of pharmacokinetic parameters (n = 28)90% confidence interval PK Parameter Ratio (%) Lower Upper Ln C_(max)106.74 96.94 117.53 Ln AUC_(inf) 110.24 103.48 117.43 Contrast is forTreatment B/Treatment A

Thus, as evidenced from the results tabulated above and illustrated inFIG. 20, the transdermal analgesic system of the present inventioncomprising a drug reservoir comprising fentanyl, are bioequivalentproducts to the rate-controlled, saturated DUROGESIC™ fentanyl system.In particular, the transdermal analgesic system according to theinvention display pharmacokinetic dynamic parameters comparable to thetransdermal DUROGESIC™ fentanyl system: the 90% confidence interval forthe average log transformed Cmax and average ratios of the testformulation versus the reference formulation fell within the 80% to 120%range. Additionally, naltrexone concentration in the serum samples werebelow the detectable levels, indicating that there was no systemicabsorption of naltrexone from the transdermal analgesic systems.

Example 32 Pharmacokinetic Studies for Transdermal Sufentanil ContainingSystems

A single-center, randomized, open-label, three-treatment, two-sequence,three-period, crass-over study in healthy subjects using IVadministration and transdermal systems was performed to estimate theamount of sufentanil absorbed from two transdermal sufentanil containinganalgesic systems of different thickness compared with intravenoussufentanil administration, and to compare the pharmacokinetics of thetwo transdermal sufentanil systems. The following treatments wereadministered during this study: Treatment A: Continuous IV sufentanilinfusion delivering 100 μg sufentanil at a rate of 10 μg/h (10 hourinfusion); Treatment B: transdermal sufentanil containing analgesicsystem (6 mg, 20 cm², 0.05 mm adhesive thickness, approximately 10 μg/h,72 hour application); and Treatment C: transdermal sufentanil containinganalgesic system (3 mg, 20 cm², 0.025 mm adhesive thickness, 10 μg/h, 72hour application).

Subjects were randomly assigned to one of two treatment sequences. Eachsubject received a continuous IV sufentanil infusion at 10 μg/h for 10hours in the first period. Following this, each subject received two72-hour transdermal systems, one system during treatment period 2 andone during treatment period 3, on naive skin sites on the upper outerarm. There was a minimum washout period of at least 6 days and not morethan 14 days between treatments. The washout period commenced uponremoval of the transdermal applications or termination of the IVinfusion. Each subject received naltrexone 50 mg tablets as the opioidantagonist starting 14 hours before system application/IV infusioninitiation. Subjects continued to receive naltrexone 50 mg tablets twicedaily during system application/IV infusion and through 24 hours postsystem removal/IV infusion termination.

At scheduled time points following IV infusion/system application, bloodsamples were collected for determination of plasma sufentanilconcentrations. During the IV treatment at pre-dose and 0.5, 1, 2, 3, 5,8, 10, 10.5, 11, 12, 14, 18, 22, 26, 30, 34, 38, and 48 hours followinginfusion initiation. During each transdermal treatment at pre-dose and0.5, 1, 2, 3, 5, 8, 12, 18, 24, 30, 36, 42, 48, 54, 60, 66, 72, 73, 74,78, 84, 96, 108, and 120 hours following system application. Plasmasamples were analyzed for determination of sufentanil concentrationusing a validated liquid chromatography-tandem mass spectrometry(LC/MS/MS) method. The Residual Sufentanil Content in the systems ismeasured using reversed-phase HPLC with UV detection. Topical skinirritation and system adherence was assessed for the transdermaltreatments. Adverse events, blood pressure, temperature, heart rate andrespiratory rate were monitored. The results of the study are tabulatedin Table 8. FIG. 21 illustrates plasma sufentanil concentrationsfollowing various sufentanil treatments, up to 120 hours after firstadministration.

Descriptive statistics were calculated for sufentanil pharmacokineticparameters for each treatment (A, B, and C) according to the statisticalmethods described in the examples above.

TABLE 8 Summary of mean (CV %) pharmacokinetic parameters Treatment B (n= 18) Treatment C (n = 18) sufentanil systems (6 mg, sufentanil systems(3 mg, 20 PK Parameter 20 cm², 0.05 mm) cm², 0.025 mm) C_(max) (ng/mL)0.34 (44) 0.31 (51) T_(max) (h) 29.3 (46) 32.0 (46) AUC₀₋₁₂₀ 19.6 (45)17.3 (45) (ng/mL · h) AUC_(inf) 21.6 (44)   19 (44) (ng/mL · h)Half-life (h) 30.5 (40) 30.3 (38)

TABLE 6A Comparative Pharmacokinetic (PK) Parameters for transdermalsufentanil containing analgesic system Input Sufentanil StandardizedNormalized Rate Size content C_(max) C_(max) (ng/ml- C_(max) (ng/ml-(mg/h) (cm²) (mg) (ng/ml) cm²) (mg/h)) 10 20 6 0.34 0.017 34 10 20 30.31 0.015 31 7.5 15 6 0.26 0.017 34 5 10 6 0.17 0.017 34 2.5 5 6 0.080.017 34 1.25 2.5 6 0.05 0.017 34

The present invention is described and characterized by one or more ofthe following features and/or characteristics, either alone or incombination with one or more of the other features and characteristics:A transdermal system for administering an analgesic through the skin,the system having a reduced potential for abuse, comprising:

(a) an analgesic reservoir comprising an analgesic, the analgesic beingselected from the group consisting of fentanyl and analogs thereof;

(b) an antagonist reservoir comprising an antagonist for said analgesic;

(c) a barrier layer, said barrier layer separating said antagonistreservoir from said analgesic reservoir, said barrier layer beingsubstantially impermeable to said analgesic and to said antagonist,wherein the system (i) substantially prevents release of the antagonistfrom the system upon securing the system to a human patient for a periodof up to about 7 days; and (ii) provides release of the antagonist at arate sufficient to provide an abuse limiting release rate ratio of theantagonist to the analgesic when the dosage form is subject to abuse,e.g., upon ingestion or substantial immersion of the system in thesolvent. The transdermal analgesic system of the invention comprises ananalgesic reservoir comprising an amount of analgesic sufficient toinduce and maintain analgesia in a human patient for a period of atleast three days, wherein the analgesic is fentanyl or an analog thereofand the analog is selected from the group consisting of alfentanil,lofentanil, remifentanil, sufentanil and trefentanil. In preferredembodiments, the analgesic is fentanyl or sufentanil, more preferably,base form of fentanyl or sufentanil. The analgesic reservoir comprises apolymeric matrix comprising about 1 wt % to about 20 wt % of theanalgesic, and optionally a permeation enhancer. The analgesic reservoirmay comprise a single phase formulation free of undissolved components;or an aqueous gel comprising up to about 20 wt % of the analgesic, about50 wt % permeation enhancer, and about 0.5 to about 10 wt % gellingagent. Additionally, the transdermal analgesic system of the inventionfurther comprises an analgesic release rate controlling means disposedbetween the analgesic reservoir and the skin.

In additional aspects, the transdermal analgesic system of the inventioncomprises an antagonist reservoir comprising an antagonist in a formthat is not releasable through the barrier layer, the antagonist beingreleasable from system when the dosage form is subject to abuse, e.g.,upon being ingested or substantially immersed in a solvent. Preferably,the antagonist reservoir comprises the antagonist dispersed within apolymer, wherein the antagonist is substantially insoluble in theantagonist reservoir polymer. The antagonist is selected from the groupconsisting of naltrexone, methyl naltrexone, naloxone, nalbuphine,nalorphine, nalorphine dinicotinate, nalmefene, nadide, levallorphan,cyclozocine and pharmaceutically acceptable salts thereof. In preferredembodiments, the antagonist is present as a salt, preferably as ahydrochloride salt of an antagonist base.

In additional aspects, the transdermal analgesic system of the inventioncomprises a barrier layer impermeable to the analgesic and theantagonist; wherein the barrier layer comprises a material which isinsoluble in water, alcohol and organic solvents. The antagonistreservoir is disposed on the skin distal surface of the barrier layerand the analgesic reservoir is disposed on the skin proximal surface ofthe barrier layer.

In additional aspects, the transdermal analgesic system of the inventionfurther comprises an antagonist release rate controlling means, whereinsaid antagonist release rate controlling means substantially preventsrelease of the antagonist from the system upon securing the system to ahuman patient for a period of up to about 7 days; and provides releaseof the antagonist at a rate sufficient to provide an abuse limitingrelease rate ratio of the antagonist to the analgesic when the dosageform is subject to abuse, e.g., upon ingestion or substantial immersionof the system in the solvent. The antagonist release rate controllingmeans is disposed on the skin distal surface of the antagonistreservoir.

In another aspect, the transdermal analgesic system of the invention,when the dosage form is subject to abuse, e.g., upon ingestion orimmersion in a solvent for a period of time, substantially continuouslyprovides a release rate ratio of the antagonist to the analgesic of atleast about 0.5:1 to about 20:1; preferably 1:1 to about 16:1, morepreferably about 1.5:1 to about 8:1; and even more preferably 2:1 toabout 4:1, wherein the period of time of immersion is up to about 1minute to about 24 hours.

In another aspect, the invention relates to a transdermal system foradministering an analgesic through the skin, the system having a reducedpotential for abuse, comprising:

(a) an analgesic reservoir comprising an amount of analgesic sufficientto induce and maintain analgesia in a human patient for a period of atleast three days, wherein the analgesic is fentanyl or an analog thereofand the analog is selected from the group consisting of alfentanil,lofentanil, remifentanil, sufentanil and trefentanil;

(b) an antagonist reservoir comprising an antagonist for said analgesic,wherein the antagonist in a form that is not releasable through thebarrier layer, the antagonist being releasable from system upon beingingested or substantially immersed in a solvent, and further wherein theantagonist is selected from the group consisting of naltrexone,methylnaltrexone, naloxone, nalbuphine, nalorphine, nalorphinedinicotinate, nalmefene, nadide, levallorphan, cyclozocine andpharmaceutically acceptable salts thereof;

(c) a barrier layer, said barrier layer separating said antagonistreservoir from said analgesic reservoir, said barrier layer beingsubstantially impermeable to said analgesic and to said antagonist; and

(d) an antagonist release rate controlling means disposed on the skindistal surface of the antagonist reservoir, wherein said antagonistrelease rate controlling means substantially prevents release of theantagonist from the system upon securing the system to a human patientfor a period of up to about 7 days, and further wherein the antagonistrelease rate controlling means provides release of the antagonist at arate sufficient to provide an abuse limiting release rate ratio of theantagonist to the analgesic when the dosage form is subject to abuse,e.g., upon ingestion or substantial immersion of the system in thesolvent.

The above-described exemplary embodiments are intended to beillustrative in all respects, rather than restrictive, of the presentinvention. Thus the present invention is capable of many variations indetailed implementation that can be derived from the descriptioncontained herein by a person skilled in the art. All such variations andmodifications are considered to be within the scope and spirit of thepresent invention.

1-103. (canceled)
 104. A transdermal patch system for administering ananalgesic through the skin, the system having a reduced potential forabuse, comprising: (a) an analgesic reservoir layer comprising ananalgesic, the analgesic being selected from the group consisting offentanyl and analogs thereof; (b) an antagonist reservoir layercomprising an antagonist for the analgesic that is dispersed within apolymer, wherein the antagonist is insoluble in the antagonist reservoirpolymer, the antagonist reservoir layer comprising an external edge ofthe system; (c) a barrier layer, the barrier layer separating theantagonist reservoir layer from the analgesic reservoir layer, thebarrier layer being impermeable to the analgesic and to the antagonist;wherein the system (i) prevents release of the antagonist from thesystem upon securing the system to a human patient for a period of up to7 days; and (ii) provides release of the antagonist at a rate sufficientto provide an abuse limiting release rate ratio of the antagonist to theanalgesic upon ingestion or immersion of the system in a solvent. 105.The system of claim 104, wherein and the analgesic is selected fromfentanyl, alfentanil, lofentanil, remifentanil, sufentanil andtrefentanil.
 106. The system of claim 104, wherein and the analgesic isfentanyl.
 107. The system of claim 104, wherein and the analgesic issufentanil.
 108. The system of claim 104, wherein the system furthercomprises: (d) an antagonist release rate controlling means, wherein theantagonist release rate controlling means includes a rate controlmembrane, a porous or a microporous membrane, or an impermeable filmwherein the release is controlled through the external edge of thesystem.
 109. The system of claim 108, wherein the antagonist releaserate controlling means is disposed on the skin distal surface of theantagonist reservoir layer.
 110. The system of claim 104, wherein theanalgesic reservoir layer comprises an amount of analgesic sufficient toinduce and maintain analgesia in a human patient for a period of atleast three days.
 111. The system of claim 107 suitable foradministration of the analgesic for at least 3 days and up to 7 days.112. The system of claim 104, wherein the analgesic reservoir layercomprises a single phase formulation free of undissolved components.113. The system of claim 104, wherein the analgesic reservoir layercomprises a polymer.
 114. The system of claim 113, wherein the polymeris an adhesive polymer.
 115. The system of claim 113, wherein thematerial forming the analgesic reservoir layer has a solubility for theanalgesic of 1 wt % to 25 wt % of the total polymer composition. 116.The system of claim 115, wherein the analgesic is fentanyl.
 117. Thesystem of claim 104, wherein the analgesic reservoir layer comprises0.05 to 1.75 mg/cm² of the analgesic.
 118. The system of claim 104,wherein the analgesic reservoir layer comprises a polymeric matrixcomprising 1 wt % to 20 wt % of the analgesic, and a permeationenhancer.
 119. The system of claim 118, further comprising an analgesicrelease rate controlling means disposed between the analgesic reservoirlayer and the skin, wherein the release rate controlling means is lesspermeable to the analgesic than to the permeation enhancer.
 120. Thesystem of claim 104, wherein the antagonist reservoir layer is disposedon the skin distal surface of the barrier layer, and the analgesicreservoir layer is disposed on the skin proximal surface of the barrierlayer.
 121. The system of claim 104, wherein the polymer of theantagonist reservoir layer is selected from polyolefin, polyethylene,polyoctene, polyvinyl acetate, polymethyl acrylate, polyethyl acrylate,polystyrene, polyethyleneoctene copolymers, ethylene-vinyl acetatecopolymer (EVA), ethylenemethyl acrylate copolymers (EMA),ethylene-acrylic acid copolymer, and ethylene-ethylacrylate copolymer.122. The system of claim 104, wherein the system exhibits a standardizedC_(max) of 0.01 to 0.2 ng/ml-cm².
 123. The system of claim 104, whereinthe system exhibits a normalized C_(max) of 3.3 to 82.5 ng/ml-(mg/h).124. The system of claim 104, wherein on administration over skin thetransdermal analgesic system exhibits a steady state analgesic flux of0.1 to 10 μg/h-cm².